MX2010008243A - 2-amino-quinoline derivatives useful as inhibitors of î²-secretase (bace). - Google Patents

Abstract

The present invention is directed to novel 2-amino-quinoline derivatives, pharmaceutical compositions containing them and their use in the treatment of Alzheimer's disease (AD), mild cognitive impairment, senility and / or dementia. The compounds of the present invention are inhibitors of β-secretase, also known as β-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2.

Description

DERIVATIVES OF 2-AMINOQUINOLINE USEFUL AS BETA-SECRETASE INHIBITORS (BACE) FIELD OF THE INVENTION The present invention is directed to novel 2-aminoquinoline derivatives, pharmaceutical compositions containing them and to their use for treating Alzheimer's disease (AD), mild cognitive impairment, senility and / or dementia. The compounds of the present invention are inhibitors of β-secretase, also known as an enzyme that divates amyloids at the β-site, BACE, BACE1, Asp2 or memapsin 2.

BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is a neurodegenerative disease associated with aging. Patients with AD suffer from cognitive deficit and loss of memory and also behavioral problems, such as anxiety. More than 90% of people with AD have the disorder sporadically while in less than 10% of cases the problem is familial or hereditary. In the United States, approximately 1 in 10 people of 65 years of age suffer from AD, while at age 85, 1 in every two people suffers AD. The average life expectancy from the initial diagnosis is 7-10 years, and patients with AD require special care provided in an assistance center, which is very expensive, or by relatives. Given the increasing number of elderly people in the population, AD is a growing medical concern. The therapies currently available for AD simply treat the symptoms of the disease and include acetylcholinesterase inhibitors to improve the cognitive and anxiolytic and antipsychotic properties to control the behavioral problems associated with this disease. The distinctive pathological characteristics in the brain of patients with AD are the neurofibrillary tangles generated by the hyperphosphorylation of the tau protein and the amyloid plaques that are formed by the aggregation of the peptide -amiloidei-42 (? ß -? ^) - A ß -? ^ forms oligomers and then fibrils and, finally, amyloid plaques. It is believed that oligomers and fibrils are especially neurotoxic and can cause most of the neurological damage associated with AD. The agents that prevent the formation of? ß -? - 42 are potentially disease modifying agents for the treatment of AD. The? ß? ^ Is generated from the amyloid precursor protein (APP) which comprises 770 amino acids. The N-terminal of ß1-42 is divated by the β-secretase (BACE), and then the β-secretase divans the C-terminal end. In addition to? ß1-42, ß-secretase also releases? ß? ^ 0 which is the predominant cleavage product in addition to? ß? -38 and? ß? -43. These forms of ß can also be added to form oligomers and fibrils. Therefore, it would be expected that inhibitors of BACE avoid the formation of? ß ^ and of? ß1-4 ?,? ß? .38 and? ß1 -43 and that they are potential therapeutic agents for the treatment of AD.

BRIEF DESCRIPTION OF THE INVENTION where a is an integer from 0 to 4; R 1 is selected from the group consisting of halogen, C 1 -alkyl, C 4 -alkoxy > halogenated d-4 alkyl and halogenated Ci_4 alkoxy; is selected from the group consisting of aryl and heteroaryl; R2 is selected from the group consisting of hydrogen and alkoxy of R3 is selected from the group consisting of hydrogen, C8 alkyl, C2-8 alkyl substituted with hydroxy, C2-8 alkyl substituted in NRARB, C ^ -Oalkyl C- alkyl, cycloalkyl, - (Ci-4 alkyl) -cycloalkyl, heterocycloalkyl and - (Ci-4 alkyl) -heterocycloalkyl; wherein RA and RB are independently selected from the group consisting of hydrogen and C1-4alkyl; A1 is selected from the group consisting of - (CH2) b-; where b is an integer from 2 to 4; L1 is selected from the group consisting of -NRC- and -C (0) -NRc-en wherein Rc is selected from the group consisting of hydrogen, Ci alkyl. 8, Ci-4 alkyl substituted with hydroxy, -Ci-4-0 alkyl-C- and C5-7 cycloalkyl; R4 is selected from the group consisting of Ci.sub.8 alkyl, C2-12 alkenyl, C-O-alkylCM alkyl, Ci-4-NRDRE alkyl, Ci-4-OH alkyl, cycloalkyl, alkyl of Ci-4-cycloalkyl, partially unsaturated carbocyclyl, -partially unsaturated C- -carbocyclyl alkyl), aryl, aralkyl, heteroaryl, C -heteroaryl alkyl, heterocycloalkyl and Ci-4-heterocycloalkyl alkyl; wherein RD and RE are independently selected from the group consisting of hydrogen and C- alkyl; and wherein the cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, C1-, -alkyl of C- -O-alkyl of C-u, carboxy, -C (O) 0-alkyl and aralkyl of alternatively, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form an annular structure selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and 1- (1, 2,3- triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or 1- (1, 2,3-triazolyl) is optionally substituted with a substituent selected from the group consisting of Ci-6 alkyl; and pharmaceutically acceptable salts thereof. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An example of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. As an example of the invention, a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier is described. To exemplify the invention there are methods of treating a disorder mediated by the β-secretase enzyme which comprises administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Other illustrative methods of the invention are those which inhibit the β-secretase enzyme and which comprise administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. An example of the invention is a method for treating a disorder selected from the group consisting of Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down syndrome, dementia associated with CVA, associated dementia. to Parkinson's disease and dementia associated with beta-amyloid, preferably, Alzheimer's disease, which comprises administering to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Another example of the invention is the use of any of the compounds described above to prepare a medicament for treating: (a) Alzheimer's disease (AD), (b) mild cognitive impairment, (c) senility, (d) dementia, ( e) dementia with Lewy bodies, (f) Down syndrome, (g) dementia associated with CVA, (h) dementia associated with Parkinson's disease and (i) dementia associated with beta-amyloid, in a subject in need of the medication .

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of Formula (I) where a, R1, R2, R3, A1, L1 and R4 are as defined herein, and pharmaceutically acceptable salts thereof. The compounds of Formula (I) are inhibitors of the enzyme β-secretase (also known as the enzyme that divates amyloids in the β-site, BACE, BACE1, Asp2 or memapsin 2), and are useful for treating Alzheimer's disease (AD) , mild cognitive impairment (MCI), senility, dementia, dementia associated with CVA, dementia with Lewy bodies, Down syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, preferably, Alzheimer's disease, cognitive impairment mild or dementia, and more preferably, Alzheimer's disease.

In one embodiment of the present invention, a is an integer from 0 to 3. In another embodiment of the present invention, a is an integer from 0 to 2. In another embodiment of the present invention, a is an integer from 1 to 2. In another embodiment of the present invention, a is 1. In one embodiment of the present invention, R1 is selected from the group consisting of halogen, Ci-4 alkoxy, halogenated Ci-4 alkyl and alkoxy In another embodiment of the present invention, R1 is selected from the group consisting of halogen, C-i-2 alkoxy, Ci alkyl. 2 Fluorinated and fluorinated C-i-2 alkoxy. In another embodiment of the present invention, R1 is selected from the group consisting of fluorine, methoxy, ethoxy, trifluoromethyl, and trifluoromethoxy. In another embodiment of the present invention, R1 is selected from the group consisting of fluorine, methoxy and ethoxy. In another embodiment of the present invention, R1 is selected from the group consisting of fluorine and ethoxy. In another embodiment of the present invention, R is selected from the group consisting of fluorine, methoxy and trifluoromethoxy; In one embodiment of the present invention, it is selected from the group consisting of aryl and heteroaryl. In another embodiment of the present invention, is selected from the group consisting of phenyl, 2-thienyl, 2-pyrrolyl, 2-pyridyl and 7-indolyl. In another embodiment of the present invention, it is selected from the group consisting of phenyl and 2-thienyl. In another embodiment of the present invention, is selected from the group consisting of phenyl, 2-thienyl and 7-indolyl. In another embodiment of the present invention, it is selected from the group consisting of phenyl and 7-indolyl. In one embodiment of the present invention, R 2 is selected from the group consisting of hydrogen and C 1-4 alkoxy. In another embodiment of the present invention, R 2 is selected from the group consisting of hydrogen and Ci-2 alkoxy. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methoxy and ethoxy. In another embodiment of the present invention, R2 is hydrogen. In another embodiment of the present invention, R 2 is selected from the group consisting of hydrogen and ethoxy. In one embodiment of the present invention, R3 is selected from the group consisting of Ci-8 alkyl, C2-8 alkyl substituted with hydroxy, C2-8 alkyl substituted in NRARB, cycloalkyl, (Ci-4 alkyl) - cycloalkyl, heterocycloalkyl and (alkyl) wherein RA and RB are independently selected from the group consisting of hydrogen and C1-4 alkyl. In another embodiment of the present invention, R3 is selected from the group consisting of cycloalkyl and heterocycloalkyl. In another embodiment of the present invention, R3 is selected from the group consisting of (S) -cyclohexyl and 4-tetrahydropyranyl. In another embodiment of the present invention, R3 is 4-tetrahydropyranyl. In one embodiment of the present invention, A1 is selected from the group consisting of - (CH2) t > -; wherein b is an integer from 2 to 4. In another embodiment of the present invention, A1 is selected from the group consisting of - (CH2) b; wherein b is an integer from 2 to 3. In another embodiment of the present invention, A1 is selected from the group consisting of -CH2CH2- and -CH2CH2CH2-. In another embodiment of the present invention, A1 is -CH2CH2-. In one embodiment of the present invention, L1 is selected from the group consisting of -NRC- and -C (0) -NRc-. In another embodiment of the present invention L1 is -C (0) -NRc-.

In one embodiment of the present invention, Rc is selected from the group consisting of hydrogen, Cis alkyl, Ci-4 alkyl substituted with hydroxy and C5-7 cycloalkyl- In another embodiment of the present invention, Rc is selected from the group which consists of hydrogen, Cie alkyl and cycloalkyl. In another embodiment of the present invention, Rc is selected from the group consisting of hydrogen, methyl, 3,3-dimethyl-n-butyl and cidohexyl. In another embodiment of the present invention, Rc is selected from the group consisting of hydrogen, 3,3-dimethyl-n-butyl and cidohexyl. In another embodiment of the present invention, Rc is selected from the group consisting of hydrogen, methyl and 3,3-dimethyl-n-butyl. In one embodiment of the present invention, R4 is selected from the group consisting of CLS alkyl, -Ci-0-alkyl of C-u, -Ci-4 alkyl-NRDRE, -alkyl of cycloalkyl, Ci-4-cycloalkyl, aryl, aralkyl, heteroaryl, Ci-4-heteroaryl alkyl, heterocycloalkyl and C 1-4 alkyl-heterocycloalkyl; wherein the cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, C-, carboxy, C- alkyl ( 0) 0-alkyl and aralkyl of d-4; and wherein RD and RE are independently selected from the group consisting of hydrogen and Ci- alkyl. In another embodiment of the present invention, R4 is selected from the group consisting of C-i.e alkyl, C-i-6 alkyl substituted with hydroxy, C-i- alkyl-Ci-4 alkyl, cycloalkyl, d-2-cycloalkyl, aralkyl, heteroaryl, Ci-2-heteroaryl alkyl, and Ci ^ -heterocycloalkyl alkyl; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group, is optionally substituted with C1.4 alkyl. In another embodiment of the present invention, R 4 is selected from the group consisting of 1- (3,3, -dimethyl-n-butyl), 1-hydroxyethyl, 1- (2,2-dimethyl-3-hydroxy-n- propyl), t-butoxyethyl, cyclohexyl, 1-adamantyl, cyclopropylmethyl, cyclohexylmethyl, benzyl, 2- (1-methylimidazolyl), 2-pyridyl-methyl, 1-pyrrolidinylethyl, 5-thiazolylmethyl and 4-morpholinylethyl. In another embodiment of the present invention, R 4 is selected from the group consisting of 1- (3,3-dimethyl-n-butyl), t-butoxyethyl, 1-adamantyl, cyclohexylmethyl, benzyl, 2- (1-methylimidazolyl) ), 2-pyridylmethyl, 1-pyrrolidinylethyl, 5-thiazolylmethyl and 4-morpholinylethyl. In another embodiment of the present invention, R 4 is selected from the group consisting of 1- (3,3-dimethyl-n-butyl), cyclohexylmethyl, benzyl, 2- (1-methylimidazolyl), 2-pyridylmethyl, 1-pyrrolidinylethyl, 5-thiazolylmethyl and 4-morpholinylethyl. In another form of the present. invention, R4 is selected from the group consisting of 1- (3,3, -dimethyl-n-butyl), 1-adamantyl, cyclohexylmethyl, 2- (1-methylimidazolyl), 5-thiazolylmethyl- and 4-morpholinylethyl. In one embodiment of the present invention, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form an annular structure selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and 1- ( 1,2,3-triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or 1- (1, 2,3-triazolyl) is optionally substituted with a selected substituent of the group consisting of C-i-6 alkyl. In another embodiment of the present invention, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form 1- (1, 2,3-triazolyl); wherein 1, 2,3-triazolyl is optionally substituted with a Ci-4 alkyl. In another embodiment of the present invention, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form 1- (4-t-butyl-1,2,3-triazolyl). Additional embodiments of the present invention include those wherein the substituents are selected for one or more of the variables defined herein, ie, a, R, R2, R3, A1, L1 and R4) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. In another embodiment of the present invention, it is any single compound or subset of compounds selected from the representative compounds listed in Tables 1-2 below. Representative compounds of the present invention are those listed in Tables 1 to 2 below. Unless otherwise indicated, where an esterogenic center is present in the listed compound, the compound was prepared as a mixture of i stereo configurations. Where a stereogenic center is present, the designations (S) - and (R) - are included to indicate that the exact stereo configuration of the center has not been determined.

Table 1. Representative compounds of Formula (I) 15 2-fluorophenyl H 4-tetrahydropyranyl 2 -C (0) -NH- t-butoxyethyl- OC 1- (3,3-dimethyl-n- 16 2-fluorophenyl H 3 4-tetrahydropyranyl 3-NH-butyl) -C (O) -18 2-fluorophenyl H 4 -tetrahydropyranyl 2 N (CH 3) - cyclohexylmethyl- OC 1- (3,3-dimethyl-n- 19 2-fluorophenyl) H 3 4-tetrahydropyranyl 2 -C (0) -NH-butyl) 21 2-thienyl H 4-tetrahydropyranyl 2 -C (0) -NH-1-adamantyl 23 2-fluorophenyl H 4-tetrahydropyranyl 2 -C (0) -NH-1-adamantyl -C (O) -N (CH 2 CH 2 2- (1- 24 2-pyrrolyl H 4 -tetrahydropyranyl 2 C (CH 3) 3) - methylimidazolyl) -C (O) -N (CH 2 CH 2 2- (1-phenyl-4-tetrahydropyranyl 2C (CH 3) 3) -methylimidazolyl) -N (CH 2 CH 2 - 26 2-fluorophenyl H 4 -tetrahydropyranyl 3 C ( CH 3) 3) -benzyl-C (O) -N (CH 2 CH 2 2- (1- 27 2-pyridyl H 4 -tetrahydropyranyl 2 C (CH 3) 3) -methylimidazolyl) -N (CH 2 CH 2-28 2-fluorophenyl H 4 -tetrah'-idropyranyl 3 C (CH 3) 3) -2-pyridylmethyl- -N (CH 2 CH 2 2- (1- 2-fluorophenyl-4-tetrahydropyranyl 3C (CH 3) 3) -methylimidazolyl) 30 2-f) uorophenyl H 4-tetrahydropyranyl 3 N (cyclohexyl) -1-pyrrolidinylethyl -C (O) -N (CH 2 CH 2 2- (1- 31 2-thienyl H 4 -tetrahydropyranyl 2 C (CH 3) 3) - methylimidazolyl) -N (CH2CH2-33 2-fluorophenyl) 4-tetrahydropyranyl 3C (CH3) 3) - 5-thiazolylmethyl- -C (O) -N (CH2CH2-34 2-fluorophenyl) 4-tetrahydropyranyl 2C (CH3) 3) -benzyl-C (O) -N (CH2CH2- 35 2-fluorophenyl-4-tetrahydropyranyl 2C (CH3) 3) -2-pyridylmethyl- -N (CH2CH2- 2- (1-36- 2-methoxyphenyl H 4 -tetrahydropyranyl 3 C (CH 3) 3) -methylimidazolyl) -C (O) -N (CH 2 CH 2 2- (1- 4-fluorophenyl-4-tetrahydropyranyl 2C (CH 3) 3) -methylimidazolyl) -C (O) - N (CH2CH2- 2- (1-38-3-fluorophenyl-4-tetrahydropyranyl 2C (CH3) 3) -methylimidazolyl) -C (O) - 4- N (CH2CH2- 2- (1-2-fluorophenyl-H-tetrahydropyranyl-2C (CH3) 3) -methylimidazolyl) 4-C (O) -2-fluorophenyl-H-tetrahydropyranyl-2N (cyclohexyl) 1-pyrrolidinylethyl-C (O) -4-N (CH2CH2-2-fluorophenyl) H-tetrapropyranyl 2 C (CH3) 3) -5-thiazolylmethyl-4-N (CH2CH2-2-fluorophenyl-H-tetrahydropyranyl 3-C (CH3 ) 3) -4-morpholinylethyl- -C (O) -4N (CH2CH2-2- (1-2-methoxyphenylH-tetrahydropyranyl 2C (CH3) 3) -methylimidazolyl) -C (O) -4N ( CH2CH2- 2- (1- 2,4-difluorophenyl-H-tetrahydropyranyl-2C (CH3) 3) -methylimidazolyl) -C (O) -4- (CH2CH2-2-fluorophenyl-H-tetrahydropyranyl-2C (CH3) 3) -4 -morpholinylethyl- -C (O) -4-N (CH 2 CH 2 2- (1-7-indolyl H tetrahydropyranyl 2 C (CH 3) 3) -methylimidazolyl) -C (O) -4- (CH 2 CH 2 2- ( 1-4-ethoxyphenyl-H-tetrahydropyranyl-2C (CH3) 3) -methylimidazolyl) -C (O) -4-N (CH2CH2-2- (1-2-ethoxyphenyl-H-tetrahydropyranyl-2C (CH3) 3) -methylimidazolyl) - 2-fluorophenyl -OCH3 tetrahydropyranyl 3 N (cyclohexyl) -4-morpholinylethyl- 4 -C (O) -2-fluorophenyl -OCH3 t 2-N-cyclohexyl-4-morpholinylethyl-C (O) -4-N (CH 2 CH 2 2- (1-3-trifluoromethylphenyl-tetrahydropyranyl-2C (CH 3) 3) -methylimidazolyl) -C (O) -4 - N (CH2CH2- 2- (1-2-trifluoromethylphenylH-tetrahydropyranyl 2C (CH3) 3) -methylimidazolyl) -C (O) -2- N- (CH2CH2- 2- (1-trifluoromethoxyphenyl H tetrahydropyranyl 2C ( CH3) 3) - methylimidazolyl) Table 2. Representative compounds of Formula (I) As used herein and unless otherwise indicated, the term "halogen" means chlorine, bromine, fluorine and iodine. Preferably, the halogen is fluorine or chlorine. More preferably, halogen is fluorine. As used herein and unless otherwise indicated, the term "alkyl", whether used alone or as part of a substituent group, includes straight and branched chains. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Similarly, the term "Ci-β alkyl" includes straight and branched chains comprising from one to eight carbon atoms.

As used herein and unless otherwise indicated, the term "halogenated C1.4 alkyl" means any Ci-4 alkyl group as defined above substituted with at least one halogen atom, preferably substituted with at least one fluorine atom. Suitable examples include, but are not limited to, -CF3, -CH2-CF3, -CF2-CF2-CF2-CF3, and the like. Similarly, the term "substituted C.sub.1 alkyl" means any C.sub.1-4 alkyl group as defined above substituted with at least one fluorine atom. Suitable examples include, but are not limited to, -CF3, -CH2-CF3, -CF2-CF2-CF2-CF3, and the like. As used herein and unless otherwise indicated, the term "alkyl substituted with hydroxy" refers to a straight or branched chain Ci-4 alkyl, wherein Ci-4 alkyl is substituted with one or more, preferably, one to three hydroxy groups, more preferably, one to two hydroxy groups, More preferably, the alkyl group of d-4 is substituted with a hydroxy group, Preferably, wherein the alkyl group of C- has a terminal carbon atom, the hydroxy group is attached to that terminal carbon atom As used herein and unless otherwise indicated, the term "alkenyl used alone or as part of a substituent group includes straight and branched chains containing at least one, preferably, one to three, and more preferably, one to two unsaturated double bonds, For example, alkenyl radicals include CH = CH2, 2-propenyl, 3-butenyl, 2-butenyl, 3,7-dimethyloctane-2,6-dienyl, and the like. Similarly, the term "C2-8 alkenyl" includes straight and branched alkenyl chains comprising from two to eight carbon atoms. As used herein and unless otherwise indicated, the term "alkynyl" used alone or as part of a substituent group includes straight and branched chains containing at least one, preferably, one to three, more preferably, from one to two and, most preferably, an unsaturated triple bond. For example, alkynyl radicals include -CCH (ie, ethynyl), 2-propynyl, 3-butynyl, and the like. Similarly, the term "C2-8 alkynyl" includes straight and branched alkynyl chains comprising from two to eight carbon atoms. As used herein and unless otherwise indicated, "alkoxy" refers to an oxygen ether radical of the straight or branched chain alkyl groups described above. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexylloxy, and the like. As used herein and unless otherwise indicated, the term "halogenated C1-4 alkoxy" means any C-alkoxy group as defined above substituted with at least one halogen atom, preferably, substituted with minus one fluorine atom. Suitable examples include, but are not limited to -OCF3, -OCH2-CF3, -OCF2-CF2-CF2-CF3, and the like. Similarly, the term "alkoxy" of fluorinated "C" means any C1-4 alkoxy group as defined above substituted with at least one fluorine atom, Suitable examples include, but are not limited to -OCF3, -OCH2-CF3, -OCF2-CF2- CF2-CF3, and the like As used herein and unless otherwise indicated, "aryl" refers to fully conjugated aromatic ring structures such as phenyl, naphthyl, and the like As used herein and less to the contrary, the term "cycloalkyl" refers to any saturated monocyclic, bicyclic, polycyclic, bridged or spiro bonded stable ring system Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl, norboranyl, adamantyl, spiropentane, 2,2,2-bicyclooctyl, and the like In addition, the term "C5.7 cycloalkyl" refers to a cycloalkyl as defined herein which contains from 5 to 7. atoms of carbon. Unless otherwise indicated, the "cycloalkyl" groups do not contain N, O or S heteroatoms. As used herein and unless otherwise indicated, the term "partially unsaturated carbocyclyl" refers to any ring system stable monocyclic, bicyclic, polycyclic, bridged or spiro-linked containing at least one carbon atom that is not part of an unsaturated bond (ie, a double or triple bond) or any bicyclic, polycyclic, bridged ring system or united by spiro, partially aromatic (for example, benzofused). Suitable examples include, but are not limited to, 1, 2,3,4-tetrahydronaphthyl, fluorenyl, 9,10-dihydroanthracenyl, indanyl, and the like. Unless otherwise indicated, the "partially unsaturated carbocyclyl" groups do not contain N, O or S heteroatoms. As used herein and unless otherwise indicated, "heteroaryl" refers to any aromatic ring structure a five- or six-member monocyclic containing at least one heteroatom selected from the group consisting of O, N and S and which, optionally, contains one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, and optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group can be attached at any ring hetero atom or carbon atom so as to generate a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, 5-tetrazolyl, and the like. As used herein, the term "heterocycloalkyl" refers to any saturated or partially unsaturated monocyclic ring structure of five to seven members that contains at least one heteroatom selected from the group consisting of O, N and S, and which optionally it contains one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a saturated, partially unsaturated or partially aromatic bicyclic ring system of nine to ten members (for example, benzofused) containing at least one heteroatom selected from the group consisting of O, N and S, and optionally containing from one to four additional heteroatoms independently selected from the group consisting of O, N and S; or a polycyclic or bridged ring system, 7 to 16 members, saturated, partially unsaturated or partially aromatic, containing at least one heteroatom selected from the group consisting of O, N and S, and optionally containing from one to four heteroatoms additionally selected independently from O, N and S. The heterocycloalkyl group can be attached at any ring hetero atom or carbon atom so as to generate a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trityanil, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, tetrahydropyranyl, azepinyl, 2,3-dihydro-1,4-benzodioxanyl, 1-aza-bicyclo [2.2.2] octanyl, 3-quinuclidinyl, and the like. As used herein, the notation "*" indicates the presence of a stereogenic center. When a particular group is "substituted" (eg, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, etc.), that group may have one or more substituents, preferably, one to five substituents, more preferably, one to three substituents and, most preferably, from one to two substituents selected independently from the list of substituents. With reference to substituents, the term "independently" means that, if it is possible to use more than one of these substituents, said substituents may be the same or different from each other. Under the standard nomenclature used throughout this discussion, the terminal portion of the designated side chain is described first, followed by functionality adjacent to the point of attachment. Accordingly, for example, a substituent "phenyl- (CrCs alkyl) -aminocarbonyl- (CrCe alkyl) -" refers to a group of Formula Unless otherwise indicated, the position at which the substituent groups of the compounds of Formula (I) are attached to the 2-aminoquinoline nucleus is indicated as follows: A person skilled in the art will recognize that some substituent groups are bivalent (ie, they are linked through two attachment points), for example, the substituent groups of A1 and L1 in the compounds of Formula (I) and the Formula (II) as described herein. A person with experience in the subject will also recognize that the bivalence of these groups is defined by the two link indicators - that is, scripts - in the list of those groups. For example, in the definition of A1, the group-Ci-4 alkyl refers to an alkyl chain comprising from one to four carbon atoms, wherein the chain is bivalent. Similarly, the group A1 -Chb-cyclopropyl- means that the group -cyclopropyl- is bivalent and, therefore, binds in the molecule in a that one carbon atom binds to the group -CH2- of A1 and the other carbon atom is attached to the remainder of the molecule as defined herein. The abbreviations used in the specification, especially the schemes and examples, are the following: CA Acetyl (ie, -C (0) -CH3) AD Alzheimer's Disease APP Amyloid precursor protein BACE Enzyme that divans amyloids at the beta BH3 THF site Borane-tetrahydrofuran complex DC Dichloromethane DIPEA or DIEA Diisopropylethylamine DMAP 4-N, N -dimethylaminopyridine DMF N, ND'methylformamide DMSO Dimethylsulfoxide EDC or EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et20 Diethyl ether EtOAc Ethyl acetate EtOH Ethanol HBTU 0-Benzotriazol-1-yl-A /, N,? ', N'-tetramethyluronium HOBT or 1-HOBt 1 -hydroxybenzotriazole HPLC High-pressure liquid chromatography LC / MS Chromatography in liquid / Mass spectrometry LH DS Lithium hexamethyldisilazide MCI Mild cognitive impairment MeOH Methanol NhUOAc NMR ammonium acetate Pd nuclear magnetic resonance (PPh3) 4 Tetrakis (triphenylphosphine) palladium OM99-2 4-amino-4-acid. { 1 - [2-carbamoyl-1 - (4- { 1- [3-carboxy- 1 - (1-carboxy-2-phenylethylcarbamoyl) -propylcarbamoyl] -etylcarbamoyl]. 2- hydroxy-1-isobutylpentylcarbamoyl) -ethylcarbamoyl] -2- methylpropylcarbamoyl-butyric t-BuOH ferc-butanol (HO-C (CH3) 3) TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran As used herein, unless otherwise indicated, the term "isolated form" means that the compound is present in a form in which it is separated from any solid mixture with another or other compounds, solvent system or biological environment . In one embodiment of the present invention, the compound of Formula (I) is present in isolated form. As used herein and unless otherwise indicated, the term "substantially pure compound" means that the mole percentage of impurities in the isolated base is less than about 5 mole percent, preferably, less than about 2 mole percent , more preferably, less than about 0.5 mole percent and, most preferably, less than about 0.1 mole percent. In one embodiment of the present invention, the compound of Formula (I) is substantially pure. As used herein, unless otherwise indicated, the term "substantially free of a corresponding salt form (s)" when used to describe the compound of Formula (I) means that the mole percentage of the The corresponding salt form (s) in the isolated base of Formula (I) is less than about 5 mole percent, preferably, less than about 2 mole percent, more preferably, less than about 0.5 mole percent , most preferably, less than about 0.1 mol percent. In one embodiment of this invention, the compound of Formula (I) is substantially free of a corresponding salt form. As used herein, the term "subject" refers to an animal, preferably, a mammal and, more preferably, a human being that has been the object of treatment, observation or experiment. The term "therapeutically effective amount", as used herein, means that the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, animal or human system that is sought by the researcher, veterinarian, doctor or other clinician, which includes alleviating the symptoms of the disease or disorder being treated. As used herein, the term "composition" encompasses a product that comprises the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combinations of specified ingredients in the specified amounts. Where the compounds according to this invention have at least one chiral center, they can therefore exist as enantiomers. When the compounds have two or several chiral centers, they can also exist as diastereomers. It should be understood that such isomers and mixtures thereof are within the scope of the present invention. Preferably, where the compound is present as an enantiomer, the enantiomer is present in an equal enantiomeric excess or greater than about 80%, more preferably, in an enantiomeric excess equal to or greater than about 90% and, even more preferably, in an enantiomeric excess equal to or greater than about 95% e, even more preferably, in an excess enantiomeric equal to or greater than about 98% and, optimally, in an enantiomeric excess equal to or greater than about 99%. Likewise, wherein the compound is present as a diastereomer, the diastereomer is present in a diastereomeric excess equal to or greater than about 80%, more preferably, in a diastereomeric excess equal to or greater than about 90%, even more preferably , in a diastereomeric excess equal to or greater than about 95%, even more preferably, in a diastereomeric excess equal to or greater than about 98% and, optimally, in a diastereomeric excess equal to or greater than about 99%. In addition, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and these should be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (eg, hydrates) or common organic solvents, and such solvates should also be encompassed within the scope of this invention. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts could be useful in the preparation of compounds according to this invention or its pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example, sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts. Accordingly, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride , edetate, edisilate, stellate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate , methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, trieiodide and valerate. Representative acids that can be used to prepare pharmaceutically acceptable salts include, but are not limited to, the following: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphoric acid, camphorsulfonic acid, (+) - (1 S) -camphor-10-sulphonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, acid citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactárico acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) - L-lactic acid, acid (±) - DL-lactic acid, lactobionic acid, maleic acid, (-) - L-malic acid, malonic acid, (+) - DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosacrylic acid, sebaic acid, acid stearic, succinic acid, sulfuric acid, tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Representative bases that can be used to prepare pharmaceutically acceptable salts include, but are not limited to, the following: ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1 H -imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. The present invention includes within its scope prodrugs of the compounds of this invention. In general, said prodrugs will be functional derivatives of the compounds, which are readily convertible in vivo to the required compound. Thus, in the methods of treatment of the present invention, the term "administer" encompasses the treatment of the various disorders indicated with the specifically described compound or with a compound that may not be specifically described, but which is converted in vivo in the specified compound after administration to the patient. Conventional procedures for selecting, and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. To provide a more concise description, some of the quantitative expressions given here are not qualified by the term "approximately". It is understood that when the term "approximately" is used, explicitly or not, the amounts given herein refer to the given real value and also refer to the approximation to such a value since it could reasonably be inferred on the basis of the ordinary experience in the matter, which includes approximations due to the experimental and / or measurement conditions for such given value. As used herein, unless otherwise indicated, the term "leaving group" means a charged or uncharged atom or group displaced during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate and the like. As used herein, unless otherwise indicated, the term "nitrogen protecting group" means a group that may be attached to a nitrogen atom to prevent such a nitrogen atom from participating in a reaction and which may be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamates - groups of the formula -C (0) OR wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2 = CH-CH2 -, and the like; amides - groups of the formula -C (0) -R ', wherein R' is, for example, methyl, phenyl, trifluoromethyl, and the like; Derivatives of N-sulfonyl - groups of the formula -SO2-R ", wherein R" is, for example, benzyl, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protection groups can be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.

As used herein and unless otherwise indicated, the term "oxygen protecting group" means a group that can be attached to an oxygen atom to protect the oxygen atom so that it does not participate in a reaction and that It can be easily removed after the reaction. Suitable examples include, but are not limited to, methyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, 1-ethoxyethyl, and the like. Other suitable nitrogen protection groups can be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Qrganic Synthesis, John Wiley & Sons, 1991. A person skilled in the art will recognize that where the reaction step of the present invention can be carried out in a variety of solvents or solvent systems, such a reaction step can also be carried out in a mixture of suitable solvents or solvent systems. . A person with experience in the field will recognize that, in the specification and claims included herein, wherein a reagent or a class / type of reagent (eg, base, solvent, etc.) is mentioned in more than one stage of a process, the individual reagents are independently selected for each reaction step and the reagents can be equal or different from each other. For example, where two steps of a process list organic or inorganic base as reactive, the organic or inorganic base selected for the first step may be the same as or different from the organic or inorganic base of the second step.

Where the processes for the preparation of the compounds according to the invention result in a mixture of stereoisomers, these isomers can be separated with conventional techniques such as preparative chromatography or recrystallization. The compounds can be prepared racemic, or individual enantiomers can be prepared by enantiospecific synthesis or by resolution. The compounds can, for example, be resolved into their enantiomeric components by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid such as tartaric acid (-) - dip-toluoyl-D- and / or tartaric acid (+) - dip-toluoyl-L- followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the helical aid. Alternatively, the compounds can be resolved using a chiral HPLC column. During any of the methods of preparing the compounds of the present invention it may be necessary or desirable to protect the sensitive or reactive groups in any of the molecules involved. This can be achieved by conventional protection groups, such as those described in Protective Groups in Orqanic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Orqanic Synthesis, John Wiley & Sons, 1999. The protecting groups can be removed at a convenient later stage with methods known in the art. Compounds with the formula (I), wherein L1 is -C (0) -NRc-, can be prepared according to the process defined in Scheme 1.

Accordingly, a compound of Formula (X) suitably substituted, a known compound or a compound prepared by known methods is reacted with diethyl ester of cyanomethylphosphonic acid, a known compound, in the presence of an organic amine such as NH4OAc, piperidine, pyridine , and the like, in the presence of an acid such as acetic acid, formic acid, β-alanine, and the like, in an organic solvent such as toluene, ethanol, methanol, and the like, to produce the corresponding compound of Formula (XI). The compound of Formula (XI) is reacted with a suitably substituted compound of Formula (XII), a known compound or a compound prepared by known methods, in the presence of a catalyst such as Cul, CuBr, and the like, in an organic solvent such as THF, diethyl ether, and the like, to produce the corresponding compound of Formula (XIII). The compound of Formula (XIII) is reacted with a compound of Formula (XIV) suitably substituted, a compound known or compound prepared by known methods, in the presence of a base such as LHMDS, lithium diisopropylamide, sodium hydride, and the like, in an organic solvent such as THF, diethyl ether, and the like, at a temperature of about 60 ° C to about 150 X, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce a mixture of the corresponding compound of Formula (XV), as a mixture of its corresponding isomers (Z) and (E). The compound of Formula (XV) is reacted with a reducing agent such as zinc, and the like, preferably zinc, in the presence of a source of protons such as ammonium chloride, calcium chloride, and the like, in an organic solvent such as methanol. , ethanol, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (XVII). Alternatively, the compound of Formula (XV) is reacted with a reducing agent such as stannic chloride, iron, and the like, in an acidic solvent such as aqueous HCl, acetic acid, and the like, at a temperature of about 60 ° C. about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (XVII). The compound of Formula (XVII) is optionally reacted with a suitable protective reagent such as acetic anhydride, acetyl chloride, and the like, according to known methods (ie, in the presence of a base such as TEA, DMAP, and the like, in an organic solvent such as dichloromethane, chloroform, and the like) to produce the compound of Formula ( XVIII) corresponding, wherein Pg1 is the appropriate corresponding nitrogen protecting group. The compound of Formula (XVIII) is reacted with an oxidizing agent such as potassium permanganate, osmium tetroxide, ruthenium tetroxide, sodium periodate, and the like, in a mixture of an organic solvent such as DCM, acetone, ethyl acetate , and the like, and water (as a cosolvent), to produce the corresponding compound of Formula (XIX). The compound of Formula (XIX) is reacted with a suitably substituted compound of Formula (XX), a known compound or compound prepared by known methods, in the presence of a coupling agent such as HBTU, EDCI, HOBT, and the like, in presence of a base such as DIPEA, TEA, pyridine, and the like, in an organic solvent such as DMF, DCM, and the like, to produce the corresponding compound of Formula (XXI). The compound of Formula (XXI) is deprotected according to known methods, for example, by reaction with hydrazine, sodium hydroxide, and the like, in a protic solvent such as methanol or ethanol, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ia). Alternatively, compounds of Formula (I), wherein L 1 is -C (0) -NRc-, can be prepared according to the process defined in Scheme 2.

Scheme 2 Accordingly, a compound of Formula (XVII) is reacted with an oxidizing agent such as potassium permanganate, osmium tetroxide, ruthenium tetroxide and sodium periodate, and the like, in a mixture of an organic solvent such as DCM, acetone, ethyl acetate, and the like, and water (as a cosolvent), to produce the corresponding compound of Formula (XXII).

The compound of Formula (XXII) is reacted by means of a two-step reaction in a vessel, first with an alkyl chloroformate such as isobutyl chloroformate, and the like, in the presence of a base such as N-methylmorpholine, DIPEA, and the like, in an organic solvent such as dichloromethane, chloroform, and the like, at a temperature of less than about room temperature, preferably, at about 0 ° C, and then with a compound of Formula (XX) suitably substituted, a known compound or a compound prepared by known methods, to produce the corresponding compound of Formula (Ia). The compounds of Formula (I), wherein L1 is -NRC-, can be prepared according to the process defined in Scheme 3 below.

Scheme 3 Accordingly, a compound of Formula (XXIII) suitably substituted (as a mixture of the corresponding isomers (Z) and (E)), wherein A ° is - (alkyl) a known compound or compound prepared by known methods, is reacted with an oxidizing agent such as potassium permanganate, osmium tetroxide, ruthenium tetroxide, sodium periodate, and the like, in the presence of N-morpholinoxide, 2,6-lutidine, and the like; in a mixture of an organic solvent such as THF, t-BuOH, 1,4-dioxane, and the like, and water (as a cosolvent), to produce the corresponding compound of Formula (XXIV) (as a mixture of the isomers ( Z) and (E) corresponding). The compound of Formula (XXIV) is reacted with a suitably substituted compound (XX), in the presence of a reducing agent such as sodium triacetoxyborohydride, and the like, in an organic solvent such as dichloromethane, dichloroethane, THF, and the like, or sodium borohydride in a protic solvent such as methanol or ethanol, or the like, to produce the corresponding compound of Formula (XXV) (as a mixture of the corresponding (Z) and (E) isomers). Alternatively, the compound of Formula (XXIV) is reacted with a suitably substituted compound (XX), in the presence of sodium cyanoborohydride, in the presence of a catalytic amount of an acid such as acetic acid, HCl, and the like in an organic solvent such as methanol, acetonitrile, and the like, to produce the corresponding compound of Formula (XXV). The compound of Formula (XXV) (as a mixture of the corresponding (Z) and (E) isomers) is reacted with a reducing agent such as zinc, and the like, in the presence of a source of protons such as ammonium chloride, chloride calcium, and the like, in an organic solvent such as methanol, ethanol, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ib). Alternatively, the compound of Formula (XXV) is reacted with a reducing agent such as stannic chloride, iron, and the like, in an acidic solvent such as aqueous HCl, acetic acid, and the like, at a temperature of about 60 ° C. about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ib). The compounds of Formula (I), wherein -A1-L1 is - (alkyl of C2-4) - RC-, can be prepared, alternatively, from the corresponding compound of Formula (le), wherein A ° is (C 1-3 alkyl) as defined in Scheme 4 included below.

Scheme 4 Accordingly, a compound of Formula (le) suitably substituted, wherein -A ° - is - (C-1-3I alkyl) -, is obtained by reaction of the compound of Formula (I) with a reducing agent selected suitably , such as borane-tetrahydrofuran, lithium aluminum hydride, and the like, in an organic solvent such as diethyl ether, THF, glime, diglyme, and the like, at a temperature of about 25 ° C to about 15 ° C, preferably , at a temperature of about 50 ° C to about 100 ° C and, optionally, in a microwave, to produce the corresponding compound of Formula (Ib). The compounds of Formula (I), wherein L 1 is -C (O) -NRc-, may alternatively be prepared according to the process defined in Scheme 5. (la) Scheme 5 Accordingly, a compound of the Formula (XIII) suitably substituted, a known compound or a compound prepared by known methods, is reacted with an oxidizing agent such as potassium permanganate, osmium tetroxide or N-methylmorpholinoxide, ruthenium tetroxide, sodium periodate or periodic acid, with ruthenium oxide, ruthenium trichloride, and the like, in a mixture of an organic solvent such as DCM, acetone, ethyl acetate , and the like, and water (as a cosolvent), to produce the corresponding compound of Formula (XXVI). The compound of Formula (XXVI) is reacted with a suitably substituted compound of Formula (XIV), a known compound or compound prepared by known methods, in the presence of a base such as LHMDS, lithium diisopropylamide, sodium hydride, and the like, in an organic solvent such as THF, diethyl ether, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably at a temperature of about 75 ° C to about 100 ° C, to produce a mixture of the compound of corresponding Formula (XXVII), as a mixture of its corresponding isomers (Z) and (E). The compound of Formula (XXVII) is reacted with a suitably substituted compound of Formula (XX), a known compound or compound prepared by known methods, in the presence of a coupling agent such as HBTU, EDCI, HOBT, and the like, in presence of a base such as DIPEA, TEA, pyridine, and the like, in an organic solvent such as DMF, DCM, and the like, to produce the corresponding compound of Formula (XXVIII).

The compound of Formula (XXVIII) is reacted with a reducing agent such as zinc, and the like, preferably zinc, in the presence of a source of protons such as ammonium chloride, calcium chloride, and the like, in an organic solvent such as methanol. , ethanol, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ia). Alternatively, the compound of Formula (XXVIII) is reacted with a reducing agent such as stannic chloride, iron, and the like, in an acidic solvent such as aqueous HCl, acetic acid, and the like, at a temperature of about 60 ° C. at about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ia). The compounds of Formula (I) can be prepared, alternatively, according to the process defined in Scheme 6 below.

'(XXVI) (XXIX) (la) Scheme 6 Accordingly, a compound of Formula (XXVI) suitably substituted, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of Formula (XX), a known compound or compound prepared by known methods, in the presence of a coupling agent such as HBTU, EDCI, HOBT, and the like, in the presence of a base such as DIPEA, TEA, pyridine, and the like, in an organic solvent such as DMF, DCM, and the like, to produce the corresponding compound of Formula (XXIX). The compound of Formula (XXIX) is reacted with a compound of Formula (XXX), wherein X is bromine, iodine or chlorine, a known compound or compound prepared by known methods, in the presence of a base such as LHMDS, diisopropylamide lithium, sodium hydride, and the like, in an organic solvent such as THF, diethyl ether, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C C, to produce a mixture of the corresponding compound of Formula (XXXI), as a mixture of its corresponding isomers (Z) and (E). The compound of Formula (XXXI) is reacted with a suitably substituted compound of Formula (XXXII), wherein the two R7 groups are the same or are hydroxy or combine to form a ring such as 4,4,5,5-tetramethyl -1, 3,2-dioxaborlane, 5,5-dimethyl-1, 3,2-dioxaborin, and the like, (ie, the compound of Formula (XXXII) is boronic acid or corresponding cyclic boronic ester), a compound known or compound prepared by known methods, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, dichloro (diphenylphosphinoferrocene) palladium, and the like, in the presence of a base such as potassium carbonate, sodium carbonate, and the like, in such a solvent as ethanol, toluene, and the like, in addition to water as a cosolvent, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 80 ° C to about 120 ° C, to produce a mixture of the corresponding compound of Formula (XXXIII), as a mixture of its isomers (Z) and (E) ) corresponding. The compound of Formula (XXXIII) is reacted with a reducing agent such as zinc, and the like, preferably zinc, in the presence of a source of protons such as ammonium chloride, calcium chloride, and the like, in an organic solvent such as methanol. , ethanol, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, a Alternatively, the compound of Formula (XXVIII) is reacted with a reducing agent such as stannic chloride, iron, and the like, in an acidic solvent such as aqueous HCl, acetic acid, and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (Ia). A person skilled in the art will recognize that the compounds of Formula (I), wherein L1 is selected from the group consisting of -N (RC) - and -C (0) -N (Rc) - and wherein Rc and R2 are taken together with the nitrogen atom to which they are attached to form an annular structure as defined herein, they can be prepared in a similar manner according to the procedures described in Scheme 1, Scheme 2, Scheme 3, Scheme 5 and Scheme 6 above by the selection of a cyclic amine suitably substituted for the compound of Formula (XX). Compounds of Formula (I), wherein A1 is -CH2CH2-, L1 is -NRC- and -Rc and R4, combine with the nitrogen atom to which they are attached to form 4-substituted-. { 1, 2,3] -triazole can be prepared according to the process defined in Scheme 7 included below.

(XXXVIII) (XXXXII) Scheme 7 Accordingly, a compound of Formula (XI) suitably substituted, a known compound or a compound prepared by known methods is reacted with a suitably protected alkyl acetate, a compound of Formula (XXXIV), wherein Pg2 is a protecting group selected suitably such as methyl, ethyl, t-butyl, benzyl, and the like, a known compound or a compound prepared by known methods, in the presence of a base such as LHMDS, lithium diisopropylamine, sodium hydride, and the like, in the presence of a catalyst such as Cul, CuBr, and the like, in an organic solvent such as THF, diethyl ether, and the like, to produce the corresponding compound of Formula (XXXV). The compound of Formula (XXXV) is reacted with a suitably substituted compound of Formula (XIV), a known compound or a compound prepared by known methods, in the presence of a base such as LHMDS, lithium diisopropylamine, sodium hydride, and the like , in an organic solvent such as THF, diethyl ether, and the like, at a temperature of from about 0 ° C to about 25 ° C, to produce the corresponding compound of Formula (XXXVI). The compound of Formula (XXXVI) can be deprotected according to known methods to produce the corresponding compound of Formula (XXXVII). For example, wherein Pg2 is fer-butyl, the compound of Formula (XXXVI) is reacted with an acid in an organic solvent (for example, with TFA in dichloromethane or HCl in an organic solvent such as diethyl ether, -propanol, ethyl acetate, and the like) to produce the corresponding compound of Formula (XXXVII). Alternatively, wherein the compound of Formula (XXXVI), Pg2 is methyl, ethyl, and the like, the compound of Formula (XXXVI) is reacted with a base such as lithium hydroxide, sodium hydroxide, and the like, in water or in water. a protic solvent such as methanol, ethanol, and the like, to produce the corresponding compound of Formula (XXXVII).

The compound of Formula (XXXVII) is reacted with a chloroformate such as ethyl chloroformate, / so-butyl chloroformate, and the like, in the presence of an organic base such as / V-methylmorpholine, DIPEA, triethylamine, and the like in a organic solvent such as THF, re-tert-butyl methyl ether, and the like, at a temperature of about -20 ° C to about 25 ° C, preferably, at a temperature of about 0 ° C to about 25 ° C. After a period of agitation, a reducing agent such as sodium borohydride, lithium borohydride, Red-Al, and the like, optionally, is added in a cosolvent such as methanol, ethanol, and the like, to produce the compound of Formula (XXXVIII) ) correspondent. The compound of Formula (XXXVIII) is reacted with a suitably selected sulfonylating agent, for example, a compound of Formula Cl-S02-RH, wherein RH is an appropriately selected alkyl or aryl group, such that CI-SO2- RH is, for example, mesyl chloride (Cl-S02-CH3), tosyl chloride (CI-S02- (4-methylphenyl)), and the like, in the presence of a base such as TEA, DMAP, and the like, in an organic solvent such as dichloromethane, chloroform, and the like, at a temperature from about -20 ° C to about 25 ° C, preferably, at a temperature from about 0 ° C to about 25 ° C, to produce the compound of Formula ( XXXIX) corresponding.

The compound of Formula (XXXIX) is reacted with sodium azide, optionally, in the presence of an iodide source such as sodium iodide, potassium iodide, and the like, in an organic solvent such as DMF, DMSO, and the like, at a temperature of about 25 ° C to about 140 ° C, preferably, at a temperature of about 25 ° C to about 60 ° C, to produce the corresponding compound of Formula (XXXX). The compound of Formula (XXXX) is reacted with a compound of Formula (XXXXI) suitably substituted, wherein RJ is selected from the group consisting of C1.5 alkyl, -Ci-4-O-alkyl of d-4, carboxy, -C (0) 0-alkyl and aralkyl of Ci-4, (preferably, RJ is selected from the group consisting of C1.5 alkyl, more preferably, RJ is t-butyl), a known compound or a compound prepared by known methods, in the presence of a catalyst such as copper sulfate, copper (II) acetate, and the like, in the presence of a base such as sodium ascorbate, ascorbic acid, DIPEA, and the like, in an organic solvent such such as DMF, THF, methanol, ethanol, and the like, in the presence of water to produce the corresponding compound of Formula (XXXXII). The compound of Formula (XXXXII) is reacted with a suitably selected reducing agent such as zinc, and the like, in the presence of a source of protons such as ammonium chloride, calcium chloride, and the like, in an organic solvent such as methanol, ethanol , and the like, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (le). Alternatively, the compound of Formula (XXXXII) is reacted with a reducing agent such as stannic chloride, iron, and the like, in an acidic solvent such as aqueous HCl, acetic acid, and the like, at a temperature of about 60 ° C. about 150 ° C, preferably, at a temperature of about 75 ° C to about 100 ° C, to produce the corresponding compound of Formula (le). The compounds of the formula (XIV) are known compounds or compounds that can be prepared according to known methods. For example, compounds of Formula (XIV) can be prepared according to the process described in Scheme 8 below.

Scheme 8 Accordingly, a compound of Formula (XXX) suitably substituted, wherein X is bromine, iodine or chlorine, a known compound or a compound prepared by known methods is reacted with a Compound of Formula (XXXII) suitably substituted, wherein the two R7 groups are the same or are hydroxy or are combined in a ring such as 4,4,5,5-tetramethyl-1,2,2-dioxaborlane, 5.5- dimethyl-1, 3,2-dioxaborin, and the like, (ie, the compound of Formula (XXXII) is the boronic acid or corresponding cyclic boronic ester), a known compound or a compound prepared by known methods, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, dichloro (diphenylphosphinoferrocene) palladium, and the like, in the presence of a base such as potassium carbonate, sodium carbonate, and the like, in a solvent such as ethanol, toluene, and the like, in addition to water as a cosolvent, at a temperature of about 60 ° C to about 150 ° C, preferably, at a temperature of about 80 ° C to about 120 ° C, to produce a mixture of the corresponding compound of Formula (XIV). The present invention further comprises pharmaceutical compositions containing one or more compounds of Formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by completely mixing the compound or compounds with a pharmaceutical carrier, in accordance with conventional pharmaceutical techniques for preparing compounds. The carrier can have a great variety of forms, according to the desired route of administration (eg, oral, parenteral). For this reason, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Solid oral preparations can also be coated with substances such as sugars or enteric coated to modulate the main absorption site. For parenteral administration, the carrier generally consists of sterile water and other ingredients can be added to increase solubility or preservation. Suspensions or injectable solutions can also be prepared using aqueous carriers together with suitable additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention are thoroughly mixed as an active ingredient with a pharmaceutical carrier according to conventional pharmaceutical techniques for preparing compounds; such a carrier can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral, as well as intramuscular. When preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and Similar; for solid oral preparations such as powders, capsules, caplets, gel capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Due to their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets can be sugar coated or enteric coated and coated by standard techniques. For parenterals, the vehicle will usually comprise sterile water, but other ingredients may be included, for example, for purposes such as aiding solubility or for preservation. Injectable suspensions may also be prepared, in which case liquid carriers, appropriate suspending agents, and the like may be employed. The pharmaceutical compositions herein, will contain, per dosage unit, for example, tablet, capsule, powder, injection, teaspoon, and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein contain, for each unit dose, for example, a tablet, capsule, powder, injection, suppository, teaspoon, and the like, of about 0.1-1000 mg and can be delivered in a dose of approximately 0.1-1000 mg. / kg / day, preferably, in a dose of about 0.5 to about 500 mg / kg / day, more preferably, in a dose of about 0.5 to about 250 mg / kg / day, with higher preferably, in a dose of about 0.5 to about 100 mg / kg / day, and more preferably, in a dose of about 1.0 to about 50 mg / kg / day. The doses, however, can be varied depending on the requirement of the patients, the severity of the condition to be treated and the compound to be used. The use of any daily administration or post-periodic dosing can be used. Preferably, these compositions are in the form of dosage units such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, measured aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or insufflation. Alternatively, the composition may be in a suitable form to be administered once a week or once a month; for example, an insoluble salt of the active compound such as the decanoate salt can be adapted to provide a slow absorption preparation for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional ingredients for preparing tablets, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, phosphate dicalcium or gums and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a salt pharmaceutically acceptable thereof. When it is said that these formulation compositions are homogeneous, it is understood that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be easily subdivided into equally effective dosage forms, such as tablets, pills and capsules. This solid preformulation composition is then subdivided into dosage unit forms of the type described above containing from 0.1 to about 1000 mg, preferably from about 0.1 to about 500 mg, of the active ingredient of the present invention. The tablets or pills of the new composition may be coated or otherwise prepared to provide a dosage form that provides the advantage of a prolonged action. For example, the tablet or pill can comprise an internal dose component and an external dose component, the latter in the form of an envelope over the previous one. The two components can be separated into an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact through the duodenum or to delay its release. A variety of material can be used for such enteric coatings or coatings, such materials include a number of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention can be incorporated are by oral administration or by injection include aqueous solutions, syrups suitably flavored, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include natural and synthetic gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. The method for treating BACE-mediated disorders described in the present invention can also be performed using a pharmaceutical composition comprising any of the compounds defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain from about 0.1 mg to 1000 mg, preferably, from about 50 to 500 mg of the compound and may be made in any suitable manner for the selected mode of administration. Carriers include necessary and pharmaceutically inert excipients that. include, but are not limited to, binders, suspending agents, lubricants, flavors, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, tablets, capsules (including, individually, a formulation of immediate release, gradual release and sustained release), granules and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions and suspensions. Useful forms for parenteral administration include solutions of sterile emulsions and suspensions. Advantageously, one or more of the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times per day. In addition, the compounds of the present invention can be administered intranasally via topical use of suitable intranasal vehicles, or via transdermal skin patches, known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, dose administration, of course, will be continuous rather than intermittent during the dosing regimen. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral inert carrier, pharmaceutically acceptable, non-toxic and suitable, such as ethanol, glycerin, water, and the like. Moreover, when desired or necessary, binders may also be incorporated into the mixture; lubricants, disintegrating agents and suitable coloring agents. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweetener, natural or synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, benzoate. sodium, acetate sodium, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Liquid forms in suitable flavored suspension or dispersing agents, such as natural and synthetic gums, for example, tragacanth, acacia, methyl cellulose, and the like. Suspensions and sterile solutions are suitable for parenteral administration. When intravenous administration is desired, isotonic preparations which generally contain suitable preservatives are used. The compounds of this invention can be administered in any of the above compositions and in accordance with the dosage regimens established in the art whenever the treatment of BACE-mediated disorders is required. The daily dose of the products can vary in a wide range of 0.01 to 10,000 mg per human adult, per day, or in any interval included in it. For oral administration, preferably, the compositions are provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dose of the patient to be treated. An effective amount of the drug is commonly provided in a dose of about 0.1-1000 mg / kg / day or any range comprised therein, preferably, in a dose of about 0.5 to about 500 mg / kg / day or any range comprised in her, more preferably, in a dose of about 0.5 to about 250 mg / kg / day or any range comprised therein, more preferably, at a dose of about 0.5 to about 100 mg / kg / day or any range comprised therein, and most preferably, in a dose of about 1.0 to about 50 mg / kg / day or any range comprised in it. The compounds can be administered in a regime of 1 to 4 times per day. The optimal doses to be administered can be readily determined by those skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration and the progress of the disease condition. In addition, factors associated with the particular patient to be treated, including age, weight, diet and time of patient administration, will result in the need to adjust the dose. A person skilled in the art will recognize that both in vivo and in vitro tests, using known and generally accepted suitable cellular and / or animal models, are predictive of the ability of a test compound to treat or prevent a daily disorder . A person with experience in the art will also recognize that human clinical trials, which include efficacy tests, dose range, first in humans, in healthy patients and / or those suffering from a given disorder, can be completed in accordance to known methods in clinical and medical techniques.

The following examples are set forth to aid in the understanding of the invention and are not intended to be limiting, nor should they be construed as limiting in any way the invention set out in the following claims. In the examples that follow, some synthetic products are listed as having been isolated as waste. The person skilled in the art will understand that the term "waste" is not limited to the physical state in which the product was isolated, and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like. .

Example 1. (Compound No. 22) 3-y3- (4-ferc-butyl- I1.2.31 triazole-1 - (tetrahydropyran-4-yl) -propin-7-ethoxy-6- (2-fluorophenyl) -quinolin -2-ilam¡na Step A. 5-Bromo-4-fluoro-2-nitrobenzaldehyde In a solution of 3-bromo-4-fluorobenzaldehyde (5.0 g, 24.6 mmol) in H2SO4 (25 mL) at 0 ° C was added nitric acid (3 mL) in H2S04 (30 mi) in drops. The resulting mixture was heated to room temperature overnight. Then, the resulting solution was poured slowly onto ice and filtered to collect the yellow precipitate. The precipitate was washed with H20 and dried, then purified by chromatography on silica gel eluted with a solvent mixture of ethyl acetate and heptanes in a ratio of 0: 100 to 25:75 to yield a light yellow solid. Step B. 6,2'-difluoro-4-nitrobiphenyl-3-carbaldehyde A solution of the yellow solid prepared as in Step A (2.0 g, 8.0 mmol), 2-fluorobenzeneboronic acid (2.3 g, 16.1 mmol) and 2 K2CO3. (12 ml) in dioxane (60 ml) was degassed with nitrogen. Pd (PPh3) 4 (0.93 g, 8.0 mmol) was added and the resulting solution was degassed again and then heated to reflux for 1 hour. The resulting mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine. After drying (MgSO4), the resulting mixture was filtered and concentrated in vacuo to yield a residue. Purification of the residue by chromatography on silica gel eluted with a solvent mixture of ethyl acetate and heptanes in a ratio of 0: 100 to 5:95 yielded a light yellow solid. Step C. 6-Ethoxy-2'-fluoro-4-nitrobiphenyl-3-carbaldehyde A solution of NaH (456 mg, 11 mmol) in EtOH (50 mL) was stirred for 30 min. The light yellow solid prepared as in Step B (600 mg, 2.3 mmol) was added and the resulting mixture was heated to 30 ° C. After 3.5 hours at 30 ° C, the bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and adsorbed directly on silica gel for purification. Purification by chromatography on silica gel eluted with a solvent mixture of dichloromethane and heptanes in a ratio of 0: 100 to 50:50 yielded a yellow solid. Step D. Diethyl ester of 1-cyano-2- (tetrahydropyran-4-yl) -vinn-phosphonic acid. Tetrahydropyran carboxaldehyde (10 g, 87.6 mmol), diethyl cyanoacetophosphonate (16.3 g, 92 mmol) was combined. , acetic acid (3 mL, 50 mmol) and ammonium acetate (3 g, 38.9 mmol) in toluene (60 mL) and the mixture was stirred overnight at room temperature, then heated to 100 ° C for two hours and heated to room temperature. filtered through MgSO4. The solvent was extracted and an oil was obtained which was purified by means of silica column chromatography (50% EtOAc / heptane) to produce an oil. Step E. 4-Cyano-5- (6-ethoxy-2'-fluoro-4-nitrobiphenyl-3-iQ-3- (tetrahydropyran-4-yl) -pent-4-enoic acid tert -butyl ester. solution of tert-butyl acetate (217 pL, 1.6 mmol) in THF (0.92 ml) at -78 ° C was added LHMDS (1.0 M in THF, 1.4 ml) slowly. After stirring for 30 min at -78 ° C, [1-cyano-2- (tetrahydropyran-4-yl) -vinyl] -phosphonic acid diethyl ester (302 mg, 1.1 mmol) dissolved in THF (0.92 ml) was added. followed by Cul (6.3 mg, 0.03 mmol). The resulting solution was warmed to room temperature, stirred for 2 h and then 6-ethoxy-2'-fluoro-4-nitrobiphenyl-3-carbaldehyde (266.0 mg, 0.9195 mmol) prepared as in Step C above was added. The resulting solution was stirred at room temperature for another 20 h. Ethyl acetate was added and the solution The resulting mixture was washed with hydrochloric acid solution (1.0 M) twice and with brine once, and then dried over magnesium sulfate. The resulting solution was filtered and concentrated. The residue was purified on a column of silica gel eluted with a solvent mixture of ethyl acetate and heptanes in a ratio of 0: 100 to 25:75 to yield a residue. MH + = 524.5 Step F. 4-Cyano-5- (6-ethoxy-2'-fluoro-4-nitrobiphenyl-3-yl) -3- (tetrahydropyran-4-yl) -pent-4-enoic acid In a solution of the residue prepared as in Step E (163 mg, 0.3119 mmol) in dichloromethane (2.0 ml) at room temperature was added TFA (1.6 ml). The resulting solution was stirred at room temperature for 1 and then concentrated. Diethyl ether was added and the resulting solution was extracted with sodium hydroxide solution (1 M) twice. The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with diethyl ether (3X). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated to produce a residue. MH + 468.47 Step G. 3- (6-Ethoxy-2'-fluoro-4-nitrobiphenyl-3-yl) -2-f 3-hydroxy-1- (tetrahydropyran-4-yl) -propyl-1-acrylonitrile In a solution of the residue prepared as in Step F (11.1 mg, 0.237 mmol) in THF (1.2 ml) at 0 ° C was added / V-methylmorpholine (30.0 pL, 16.6 mmol) and then ethyl chloroformate was added (0.26 pL, 0. 27 mmol) slowly. The resulting solution was stirred at 0 ° C for 1 h, and then sodium borohydride (0.45 mg, 1.2 mmol) was added. Methanol (0.2 ml) was added slowly in the resulting solution which was then stirred at room temperature for 2 h. Ethyl acetate was added. The resulting solution was washed with hydrochloric acid (1.0 M) twice and with brine once and then dried over magnesium sulfate. The resulting solution was filtered and concentrated to produce a yellow oil. The yellow oil was purified on a column of silica gel eluted with a solvent mixture of ethyl acetate and heptanes in a ratio of 0: 100 to 35:65 to yield a yellow solid. MH + = 454.49 Step H. 2- [3-azido-1- (tetrahydropyran-4-yl) -propyl-1-3- (6-ethoxy-2'-fluoro-4-nitrobiphenyl-3-yl) -acrylonitrile In a solution of the yellow solid prepared as in Step G and triethylamine (41 pL, 0.295 mmol) in dichloromethane (1 mL) at 0 ° C was added methanesulfonyl chloride (12.4 pL, 0.16 mmol) slowly. The resulting solution was stirred at 0 ° C for 30 min and then at room temperature for 30 min. The resulting solution was diluted with dichloromethane, washed with hydrochloric acid solution (1.0 M) and dried over magnesium sulfate. Then, the resulting solution was filtered and concentrated. The residue was dissolved in DMF (1.2 ml); Sodium azide (43.5 mg, 0.67 mmol) was added and the resulting solution was stirred at 50 ° C for two hours. The resulting mixture was concentrated in vacuo, loaded directly onto silica gel and purified by means of elution with ethyl acetate and heptanes in a ratio of 0: 100 to 25:75 to produce a foamy solid. MH + 479.50 Step I. 2-r3- (4-tert-butyl-f1.2,31tr-azole-1-yl) -1- (tetrahydropyran-4-yn-propyl-3- (6-ethoxy) -2'-fluoro-4-nitrobophenyl-3-yl) -acrylonitrile In a suspension of the foamed solid prepared as in Step H (0.056 g, 0.117 mmol) in EtOH (0.8 ml), a minimum amount of THF was added. to solubilize the compound, then 3,3-dimethyl-1-butyne (87 pL, 0.70 mmol), sodium ascorbate (0.0046 g, 0.023 mmol) and copper (II) sulphate pentahydrate (1.5 mg, 0.006 mmol) were added. and then a minimum amount of H2O to maintain solubility.The resulting mixture was stirred at room temperature in the dark.Additional amount of 3,3-dimethyl-1-butyne (87 μ?) was added two more times in intervals of Half an hour and the resulting mixture was stirred overnight, ethyl acetate was added and the resulting solution was washed with a saturated sodium bicarbonate solution, water and brine and then dried over magnesium sulfate to produce a residue. The residue was purified by chromatography on silica gel, eluted with ethyl acetate and heptanes in a ratio of 0: 100 to 35:65 to yield a yellow foamy solid. MH + = 561.65 Step J. 3-r3- (4-tert-butyl-f1, 2,3-triazol-1-yl) -1- (tetrahydroDiran-4-yl) -Dropin-7-ethoxy-6- (2- fluorophenyl) -quinolin-2-ylamine In a microwave flask was combined the yellow foamy solid prepared as in Step I (0.0047 g, 0.084 mmol), Zn powder (180 mg) and solid ammonium chloride (29 mg) in MeOH . The resulting mixture was heated in a microwave at 95 ° C for 20 minutes. The resulting solution was filtered through Celite®, washed with MeOH and dichloromethane was added after which it was concentrated in vacuo to yield a residue. The residue was purified by chromatography on silica gel, eluted with ethyl acetate and MeOH in a ratio of 100: 0 to 90:10 to yield the title compound as a white solid. Hydrochloric acid in diethyl ether was added and the resulting solution was concentrated to yield the title compound as its corresponding HCI salt in the form of a light yellow solid. MH + = 531.66 1 H NMR free base (300 MHz, MeOD): 51.15 (s, 9 H), 1.30-1.35 (m, 7 H, 1.71-1.86 (m, 2 H), 2.37-2.6 (m, 1 H ), 2.72-2.88 (m, 1 H), 3.31-3.41 (m, 2 H), 3.82-3.87 (m, 1 H), 3.95-3.97 (m, 1 H), 4.14 (q, J = 6.78 Hz , 2 H), 4.24-4.36 (m, 2 H), 7.04 (s, 1 H), 7.10 - 7.25 (m, 2 H), 7.34 - 7.41 (m, 2 H), 7.53 (s, 2 H) 7.89 (s, 1 H) Example 2. (Compound No. 47) 4-r 2 -amino-6- (2-fluorophenyl) -quinolin-3-ill-N- (3,3-dimethylbutyl) -N- (2-morpholine ^ ethyl) -4 - (tetrahydropyran-4-yl) -butyramide Step A. [1-Cyano-2- (tetrahydropyran-4-yl) -hex-5-enyl-phosphonic acid diethyl ester.) In a flask, Mg (5.7 g) in THF (50 ml) was placed in an iodine flake. . The reaction mixture was stirred vigorously and warmed slightly as 4-bromobutene (25 mL) was added. After consuming the Mg metal, the resulting solution was placed with a cannula in a flask containing a mixture of [1-cyano-2- (tetrahydropyran-4-yl) -vinyl] -phosphonic acid diethyl ester ( 21.78 g, 79.7 mmol) prepared as described in Example 1, Step D above and then Cul (0.3 g) was added with THF (30 mL). The resulting mixture was stirred for three hours. A solution of saturated aqueous NH 4 Cl and ethyl acetate was added. The organic layer was separated and dried with MgSO 4, filtered and evaporated in vacuo to yield an oil.

Step B. 5-Cyano-5- (diethoxyphosphoryl) -4- (tetrahydropyran-4-yl) -pentanoic acid In a solution of [1-cyano-2- (tetrahydropyran-4-yl) - diethyl ester hex-5-enyl] -phosphonic acid (6.26 g, 19.0 mmol) in dichloromethane (211 ml), H2O (173 ml) and acetic acid (73 ml) was added tetrabutylammonium bromide (127 mg) followed by the addition of KMnO4 in portions. The resulting mixture was stirred at room temperature overnight. The resulting viscous solution was cooled to 0 ° C and NaHS03 was added slowly until the mixture cleared. The layers were separated and the organic layer was dried over magnesium sulfate, it was filtered and concentrated to produce a residue. Heptanes were added and the resulting mixture was concentrated to produce a residue. MH + 347.35 Step C. 5-Bromo-2-nitrobenzaldehyde. Sulfuric acid (108 ml) and 3-bromobenzaldehyde (25 g, 0.135 mol) were cooled to 0 ° C in a flask. Potassium nitrate (14.3 g, 0.14 mol) was added in the resulting mixture, in portions, for 1 h. The resulting mixture was stirred another 2 h at 0 ° C. The obtained mixture was poured into 2 I of ice and filtered to yield a solid. The solid was purified by chromatography on silica (330 g, 30% Et 2 O / heptane) to produce a residue which was recrystallized from EtOAc / heptane to produce a solid. Step D. 2'-Fluoro-4-nitrobiphenyl-3-carbaldehyde A solution of 5-bromo-2-nitrobenzaldehyde (8.2 g, 36 mmol), 2-fluorobenzeneboronic acid (10.0 g, 71.6 mmol) and 2M K2C03 (54 ml) ) in dioxane (250 ml) was degassed with nitrogen. Pd (PPh3) 4 (3.9 g, 3.6 mmol) was added and the resulting mixture was degassed again and heated to reflux for 90 minutes. Then, the resulting mixture was diluted with EtOAc and washed with an aqueous saturated NaHCO3 solution and brine. The EtOAc extract was dried with MgSO 4, filtered and concentrated in vacuo to yield a residue. The residue was purified by chromatography on silica gel eluted with ethyl acetate and heptanes in a ratio of 0: 100 to 5:95 to yield a yellow solid. 1 H NMR (300 MHz, CDCl 3): 57.19-7.33 (m, 2 H), 7.4-7.53 (m, 2 H), 7.94 (dt, = 8.29, 1.88 Hz, 1 H), 8.1 1 (s, 1 H ), 8.22 (d, J = 8.67 Hz, 1 H), 10.50 (s, 1 H) Step E. 5-Cyano-6- (2'-fluoro-4-nitrobiphenyl-3-yl) -4- acid ( tetrahydropyran-4-yl) -hex-5-enoic acid in a solution of the residue prepared as in Step B (6.7 g, 19.2 mmol) in THF (385 mi) at -78 ° C was added LHMDS (1.0 M in THF, 41 mi) slowly. After stirring for 30 min at -78 ° C, the resulting mixture was warmed to room temperature and the yellow solid prepared as in Step D (4.7 g, 19.2 mmol) was added. The resulting solution was stirred at room temperature for another 20 h. Ethyl acetate was added and the resulting solution was washed with hydrochloric acid solution (1.0 M) and with brine, and then dried over magnesium sulfate. The resulting solution was filtered and concentrated to produce a residue. The residue was purified on a column of silica gel eluted with a solvent mixture of dichloromethane and MeOH (95: 5) to yield a brown solid. MH + = 438.45 Step F. (3,3-dimethylbutyl) - (2-morpholin-4-yl-ethyl) -amine 4- (2-chloroethyl) -morpholine was placed in a microwave reactor. (1.5 g, 8.1 mmol), 3,3-dimethylbutylamine (2.2 ml, 16 mmol), diisopropylethylamine (3.1 ml, 18 mmol) and acetonitrile (30 ml). The resulting mixture was microwaved at 130 ° C for 30 minutes and then diluted with dichloromethane and 1N sodium hydroxide The layers were separated and the organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated to produce an orange oil. The oil was purified on a column of silica gel and eluted with 15% of 10: 1 (MeOH: NH 4 OH) in EtOAc to yield a yellow oil. 1 H NMR (300 MHz, CDCl 3) 60.87-0.94 (m, 9 H), 1.35-1.46 (m, 2 H), 2.42-2.51 (m, 8 H), 2.58-2.66 (m, 1 H), 2.72 ( t, J = 6.03 Hz, 1 H), 3.67- 3.74 (m, 4 H) Step G. 5-Cyano-6- (2'-fluoro-4-nitrobiphenyl-3-yl) -4- (tetrahydropy) ran-4-yl) -hex-5-enoic (3,3-dimethylbutyl) - (2-morpholin-4-yl-ethyl) -amide In a solution of the solid prepared as in Step E (3.2 g, 7.3 mmol) in DMF (30 mL) was added the yellow oil prepared as in Step F (1.7 g, 8.0 mmol), HBTU (4.1 g, 10.9 mmol) and DIEA (3.8 mL, 21.8 mmol). The resulting mixture was stirred for 24 hours at room temperature, and then diluted with EtOAc. The resulting solution was washed with Saturated aqueous NaHC03 and with brine several times, then dried over magnesium sulfate and concentrated to obtain a foamy solid. The foamed solid was purified on silica gel and eluted with a solvent mixture of dichloromethane and MeOH in a ratio of 100: 0 to 96: 4 to produce a brown solid. MH + 634.78. Step H. 4-i2-Amino-6- (2-fluorophenyl) -quinolin-3-yl-N- (3,3-dimethylbutyl) -N- (2-morpholin-4-yl-ethyl) -4- ( tetrahydropyran-4-yl) -butyramide A mixture of the brown solid (2.25 g, 3.7 mmol) prepared as in Step G above, zinc powder (25 g), ammonium chloride (7.8 g), MeOH (90 ml) and THF (17 mL) was heated to reflux. After three hours, the resulting mixture was cooled to room temperature, filtered through Celite® and washed with MeOH / dichloromethane. The filtrate was concentrated to yield a solid which was purified on a silica gel column and eluted with 10% of 10: 1 (MeOH: NH 4 OH) in EtOAc to afford the title compound as a yellow solid. The HCl salt of the title compound was prepared by dissolving the yellow solid (506 mg) in a small amount of ethanol and concentrating with 1 M HCl / diethyl ether (3X) to yield a white solid. LCMS MH + 604.80 1H NMR (HCl salt) (300 MHz, MeOD) d 1.31 (d, J = 7.54 Hz, 2 H), 1.39-1.54 (m, 3 H), 1.99 (s, 3 H), 2.28- 2.44 (m, 3 H), 2.96 (s, 1 H), 3.14- 3. 28 (m, 4 H), 3.37 (d, J = 3.01 Hz, 1 H), 3.46 (s, 1 H), 3.58-3.72 (m, 4 H), 3.78 -3.93 (m, 3 H), 3.99 -4.1 1 (m, 3 H), 7.25-7.37 (m, 2 H), 7.43-7.52 (m, 1 H), 7.60 (td, J = 7.72, 1.88 Hz, 1 H), 7.80 (d, = 8.67 Hz, 1 H), 7.99-8.05 (m, 1 H) ,. 8.16 (s, 1 H), 8.54 (s, 1 H) Example 3. (Compound No. 43) 3-r4-f (3,3-dimethylbutyl) - (2-morpholin-4-yl-ethyl) -amino1-1- (tetrahydropyran-4-yl) -butyl-6- (2-fluorophenyl) -quinolin-2-ylamine In the white solid (1.13 g, 1.9 mmol) prepared as in Example 2, Step H above in THF (190 ml) was added BH 3 THF (1 M in THF, 28 ml). The resulting mixture was degassed with nitrogen and then heated to reflux. After 2.5 hours, the resulting mixture was cooled to room temperature and HCl was added slowly until the pH was < 5. The resulting mixture was heated again to reflux for 30 minutes, then cooled to room temperature and concentrated in vacuo to produce a residue. The residue was adsorbed directly on silica gel in MeOH and purified by means of 10% elution of 10: 1 (MeOH: NH40H) in EtOAc to produce a second residue. The second residue was purified by Gilson HPLC (gradient elution from 20:80 CH3CN / H2O / 0.1% TFA to 75:25 CH3CN / H2O / 0.1% TFA) to yield the title compound as its corresponding TFA salt . The concentrated product was dissolved in a small amount of EtOH and concentrated with 1 HCl / diethyl ether (3X) and then concentrated with diethyl ether (2X) in EtOH to yield the title compound as a white solid, in the form of its corresponding HCI salt. LCMS MH + 590.81 H NMR (300 MHz, MeOD): 00.88 (s, 9 H), 1.19 (t, .7 = 7.16 Hz, 2 H), 1.35-2.0 (m, 9 H), 2.96-3.54 (m, 13 H), 3.37-3.68 (m, 4 H), 3.62 (q, J = 7.03 Hz, 4 H), 3.90-4.06 (m, 4 H), 7.25-7.38 (m, 2 H), 7.44 - 7.52 (m, 1 H), 7.61 (td, J = 7.82, 1.70 Hz, 1 H), 7.79 (d, J = 8.67 Hz, 1 H), 8.02 (d, J = 8.67 Hz, 1 H), 8.19 ( s, 1 H), 8.57 (s, 1 H) Example 4. (Compound No. 31) 4- (2-amino-6-thiophen-2-yl-quinolin-3-yl) -N- (3,3-dimethylbutyl) -N- (1-methyl- 1 H- imidazol-2-methylmethyl) -4- (tetrah -dipran-4-yl) -butyramide Step A. (3,3-dimethylobutyl) - (1-methyl-1 H-imidazol-2-ylmethyl) -amine A solution of 1-methyl-2-imidazolecarboxaldehyde (4 g, 0.036 mol) and 3,3-dimethylbutylamine (4.9 ml, 0.036 mol) in MeOH (100 ml) was stirred at room temperature for 1 hour before adding NaBH 4 (2.0 g, 0.053 mol) in portions. The resulting solution was stirred at room temperature for another hour before cooling it rapidly with water. The MeOH was removed under vacuum from the resulting mixture and the residue was purified by column chromatography (0-15% MeOH / EtOAc) to produce a light yellow liquid. MH + 196.2 Step B. Acid diethyl ester [1-cyano-4 - [(3,3-dimethylbutyl) - (1-methyl-1 H-imidazol-2-ylmethyl) -carbamoin-2- (tetrahydropyran-4-yl) - butyn-phosphonic acid In a solution of the light yellow liquid cooled with ice and prepared as in Step A above (1.8 g, 9 mmol), 5-cyano-5- (diethoxyphosphoryl) -4- (tetrahydropyran-4) -yl) -pentanoic acid (3.0 g, 8.7 mmol, prepared as described in Example 2, Step B) and HOBT (1.5 g, 11 mmol) in CH2Cl2 (100 mL) was added TEA (2.4 mL) followed by addition of 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC, 2.2 g, 11 mmol). The resulting mixture was allowed to warm to room temperature and was stirred overnight. EtOAc (200 mL) was added. The resulting solution was washed with dilute HCl solution (approximately 0.1 N, 50 ml), saturated aqueous NaHCO 3 solution and then with brine. The organic layer was dried with MgSO 4, and the EtOAc was evaporated to yield an oil. MH + 525.5 Step C. 6- (5-Bromo-2-nitrophenyl) -5-cyano-4- (tetrahydropyran-4-yl) -hex-5-enoic acid (3,3-dimethylbutyl) - (1-methyl-) 1 H-imidazol-2-methylmethyl) amide In an ice-cooled solution of the oil prepared as in Step B above (2.2 g, 4.2 mmol) in THF (10 mL) was added LHMDS (1.0M in THF, 5.0 mi) and the resulting solution was stirred for 10 min. 5-Bromo-2-nitrobenzaldehyde (1.0 g, 4.2 mmol, synthesized as described in Example 2, Step C) in THF (10 mL) was added and the resulting solution was allowed to warm to room temperature after which it was stirred overnight. The reaction was rapidly quenched with an aqueous solution of NH 4 Cl and the The resulting solution was extracted with EtOAc. The organic layer was dried with MgSO 4. The EtOAc was evaporated to produce an oil. MH + 600.2, 602.3 Stage D. 6- (5-Bromo-2-nitrophenyl) -5-cyano-4- (tetrahydropyran-4-yl) -hex-5-enoic acid (3,3-d-methylbutyl) - (1-methyl-1 H-imidazol-2-ylmethyl) -amide A solution of the oil prepared as in Step C (0.2 g, 0.33 mmol), 3-thiopheneboronic acid (0.045 g, 0.34 mmol), tetrakis (triphenylphosphine) ) palladium (0) (0.02 g) and K2CO3 (0.092 g) in toluene / EtOH / water (5/2/1 ml) was heated for one hour at reflux. EtOAc (100 mL) was added and the resulting solution was washed with saturated aqueous NaCl solution. The organic layer was dried with MgSO4 > and the EtOAc was evaporated to produce an oil. MH + 605 Step E: 4- (2-amino-6-thiophen-2-yl-quinolin-3-yl) -N- (3,3-dimethylbutyl) -N- (1-methyl-1 H-imidazole) -2-ylmethyl) -4- (tetrah -dropiran-4-yl) -butyramide A mixture of the oil prepared as in Step E above (0.2 g, 0.33 mmol), Zn powder (0.3 g) and NH4CI (0.06 g) in MeOH (5 ml) was heated in the microwave at 130 ° C for 5 min. The resulting solid was removed by filtration and the filtrate was concentrated under vacuum to produce an oil. The oil was purified by Gilson HPLC to produce the title compound as its corresponding TFA salt in the form of a white solid. MH + 574.3 1 H NMR (300 MHz, MeOD) d 0.73 (s, 9 H), 1.17-1.55 (m, 6 H), 1.90-2.07 (m, 4 H), 2.27-2.45 (m, 3 H), 2.92 (br s, 1 H), 3.36 (d, J = 3.01 Hz, 1 H), 3.46 (t, J = 1 1.11 Hz, 1 H), 3.86 (s, 3 H), 3.91 (br s, 1 H), 4.03 (dd, J = 11.87, 3.58 Hz, 1 H), 4.61 - 4.81 (m, 2 H), 7.44 (d, J = 1.88 Hz, 1 H), 7.49 (d, J = 1.88 Hz, 1 H), 7.60 (d, J = 1.88 Hz, 2 H), 7.78 ( d, J = 8.67 Hz, 1 H), 7.83 (t, J = 2.26 Hz, 1 H), 8.10 - 8.23 (m, 2 H), 8.45 (s, 1 H).

Example 5. (Compound No. 51) 4-f2-amino-6- (2-ethoxyphenyl) -quinolin-3-yl-1-N- (3,3-dimethylbutyl) -N- (1-methyl-1 H-imidazole-2 -ylmethyl) -4- (tetrahydropyran-4-yl) -butyramide Step A. 5-Cyano-6- (2'-ethoxy-4-nitrobiphenyl-3-yl) -4- (tetrahydropyran-4-yl) -hex-5-enoic acid (3,3-dimethylbutyl) - (1-methyl) -1 H-imidazol-2-ylmethyl) -amide A solution of the oil prepared as in Example 4, Step C above (0.17 g, 0.28 mmol), 2-ethoxybenzyl boronic acid (0.063 g, 0.3 mmol), tetrakis (triphenylphosphine) palladium (0) (0.02 g) and K2C03 (0.08 g) in toluene / EtOH / water (3/3/1 ml) was heated to reflux overnight. EtOAc (100 mL) was added and the resulting solution was washed with aqueous NaCl solution saturated The organic layer was dried over MgSO4 and the EtOAc was evaporated to produce an oil. MH + 642.5 Step B: 4rf2-amino-6- (2-ethoxyphenyl) -quinolin-3-in-N- (3,3-dimethylbutyl) -N- (1-methyl-1H-imidazol-2-ylmethyl) ) -4- (tetrahydropyran-4-yl) -butyramide A mixture of the oil prepared as in Step A above (0.13 g, 0.2 mmol), Zn powder (0.2 g) and NH4CI (0.06 g) in MeOH (5 ml) ) was heated in a microwave at 130 ° C for 5 min. The resulting solid was removed by filtration and the filtrate was concentrated under vacuum to produce an oil. The oil was purified by Gilson HPLC to produce the title compound as its corresponding TFA salt in the form of an off-white solid. MH + 612.5 H NMR (300 MHz, MeOD) d 0.62 (s, 9 H), 1.15 (d, J = 3.39 Hz, 3 H), 1.22 (t, J = 6.97 Hz, 3 H), 1.27-1.47 (m , 3 H), 1.75-1.97 (m, 4 H), 2.26 (s, 4 H), 2.81 (br s, 1 H), 3.28 (br s, 1 H), 3.74 (s, 3 H), 3.79 (br s, 1 H), 3.87-3.95 (m, 1 H), 3.99 (q, J = 7.03 Hz, 2 H), 4.55-4.67 (m, 2 H), 6.91 -7.05 (m, 2 H) , 7.26 (d, J = 7.54 Hz, 2 H), 7.33 (d, J = 1.88 Hz, 1 H), 7.38 (d, = 1.88 Hz, 1 H), 7.62 (d, J = 8.67 Hz, 1 H ), 7.88-7.96 (m, 2 H), 8.35 (s, 1 H) Example 6. In vitro BACE assay-1 This test was performed by means of CEREP (catalog Ref 761-B, referred to SOP No. 1 C131; ERMOLIEFF, J., LOY, JA, KOELSCH, G. and TANG , J., Proteolytic activation of recombinant pro-memapsin 2 (pro BACE) studied with new fluorogenic substrates, Biochemistry, (2000) Vol. 39, p. 12450). More specifically, the assay performed in 50 μ? _ In a 96-well plate evaluated the effect of the test compound on the quantified human BACE-1 activity by measuring the formation of Mca-SEVNL-NH2 from Mca-SEVNLDAEFRK (Dnp) -RR-NH2 with a recombinant enzyme. The compound of the test, the reference compound or water (control) was added in a buffer containing 0.09 M sodium acetate (pH 4.5) and 0.25 pg BACE-1. The interference of the compound with the fluorimetric detection method due to autofluorescence was controlled by measurements at the defined wavelengths to evaluate the activity of the enzyme. Then, the reaction was initiated by the addition of 7.5 μ? of the substrate Mca-S-E-V-N-L-D-A-E-F-R-K (Dnp) -R-R-NH2 and the mixture was incubated for 60 min at 37 ° C. For the initial control measurement the substrate was omitted from the reaction mixture. Immediately after the incubation, the intensity of the fluorescence emitted by the reaction product Mca-S-E-V-N-L-NH2 was measured at Aex = 320 nm and Aem = 405 nm with a microplate reader (Ultra, Tecan). The standard inhibitory reference compound was OM99-2, which was tested in each experiment at different concentrations to obtain an inhibition curve from which its IC50 value was calculated.

The representative compounds of the present invention were tested in the assay described above and the results are listed in Table 3 below.

Table 3.% inhibition and ICso ID No. ICso (μ?)% Inh to 1 μ? % lnh to 10 μ? 1 34 2 59 3 35 4 71 5 6 > 5.00 43 7 0.26 83 8 9 126 10 0.83 47 1 1 28 12 0.35 74.5 13 77 14 15 0.54 113 16. > 0.62 88 17 1.40 73 18 77 19 14 20 0.89 92 21 0.69 87 22 0.15 65 23 0.57 97 24 1.40 93 25 0.32 72 26 27 1.8 91 28 0.88 74 29 1.50 54 30 31 0.42 79 98 33 34 0.39 68 35 0.33 116 36 0.50 76 37 82 38 0.47 69 39 0.35 93 41 0.45 65 42 0.32 65 43 78 45 0.53 94 46 0.36 70 47 0.37 58 49 99 50 22 51 0.32 99 52 3.60 55 53 2.20 55 54 8 55 2.40 90 56 73 Example 7. In vivo test The compounds of the present invention can also be tested for their effectiveness in the treatment of disorders mediated by the BACE enzyme, for example, Alzheimer's disease, by testing the compounds in an in vivo assay, for example, as described in Sirinathsinghji, DJS (Merck Sharp and Dohme Research Laboratories, Neuroscience Research Center, Essex, UK), Transgenic mouse models of Alzheimer's disease, Biochemical Society Transactions (1998), 26 (3), p. 504-508; Van Leuven, F. (Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology (VIB), KU Leuven, Louvain, Belg.), Single and multiple transgenic mice as models for Alzheimer's disease, Progress in Neurobiology (Oxford) ( 2000), 61 (3), p. 305-312; Hsiao, K .; Chapman, P .; Nilsen, S .; Eckman, C; Harigaya, Y .; Younkin, S .; Yang, F .; Cole, G. (Dep. Neurology, Univ. Minnesota, Minneapolis, MN, USA), Correlative memory deficits, A3 elevation, and amyloid plagues in transgenic mice. Science (Washington, D.C.) (1996), 274 (5284), p. 99-102 (Tg2576 mice); Oddo, S .; Caccamo, A .; Shepherd, J. D .; Murphy, M. P .; Golde, T. E .; Kayed, R .; Metherate, R .; Mattson, M. P .; Akbari, Y .; LaFerla, FM (Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA), Triple-transgenic model of Alzheimer's disease with plagues and tangles: Intracellular A3 and synaptic dysfunction, Neuron (2003), 39 (3), pag. 409-421 (Triple Transgenic Mice APP); Ruberti, F .; Capsoni, S .; Comparini, A .; Di Daniel, E .; Franzot, J .; Gonfloni, S .; Rossi, G .; Berardi, N .; Cattaneo, A. (Neuroscience Program, International School for Advanced Studies (SISSA), Trieste, Italy), Phenotypic knockout of nerve growth factor in adult transgenic mice reveal severe deficits in basal forebrain cholinergic neurons, cell death in the soleen, and skeletal muscle dvstrophv, Journal of Neuroscience (2000) , 20 (7), p. 2589-2601 (AD11 mice); Games, D .; Adams, D .; Alessandrini, R .; Barbour, R .; Berthelette, P .; Blackwell, C; Carr, T. Clemens, J. Donaldson, T .; and others (Athena Neurosciences, Inc., South San Francisco, CA, USA), Alzheimer-type neuropathology in transgenic mice overexpressing V717F 3-amyloid precursor protein. Nature (London) (1995), 373 (6514), p. 523-7 (V717F mice); Nevé, R. L; Boyce, F. M .; McPhie, D. L; Greenan, J .; Oster-Granite, ML (Dep. Genetics, Harvard Medical School and McLean Hospital, Belmont, MA, USA), Transgenic mice expressing APP-C100 in the brain, Neurobiology of Aging (1996), 17 (2), p. . 191-203 (APP-C100 mice); and / or as described in U.S. Pat. no. 5,811, 633; U.S. patent no. 5,877,399; U.S. patent no. 5,672,805; U.S. patent no. 5,720,936; U.S. patent no. 5,612,486; U.S. patent no. 5,580,003; U.S. patent no. 5,850,003; U.S. patent no. 5,387,742; U.S. patent no. 5,877,015; U.S. patent no. 5.81 1, 633; U.S. patent no. 6,037,521; U.S. patent no. 6,184,435; U.S. patent no. 6,187,922; U.S. patent no. 6,211, 428 and U.S. Pat. no. 6,340,783.

Example 8. Testing in humans The compounds of the present invention can also be tested for their effectiveness in the treatment of disorders mediated by the BACE enzyme, for example, Alzheimer's disease, by testing the compounds in humans, for example, as described in Lins, H .; Wichart, I. Bancher, C. Wallesch, C.-W .; Jellinger, K. A .; Roesler, N. (Department of Neurology, Otto-von-Guericke-University, Magdeburg, Germany), Immunoreactivities of amyloid ß peptide (1-42) and total T protein in lumbar cerebrospinal fluid of patients with normal pressure hvdrocephalus, Journal of Neural Transmission (2004), 11 1 (3), p. 273-280; Lewczuk, P .; Esselmann, H .; Otto, M .; Maler, J. M .; Henkel, A. W .; Henkel, M. K .; Eikenberg, O .; Antz, C; Krause, W.-R .; Reulbach, U. ¡Kornhuber, J .; Wiltfang, J. (Department of Psychiatry and Psychotherapy, Molecular Neurobiology Lab, University of Erlangen-Nuremberg, Erlangen, Germany), Neurochemical diagnosis of Alzheimer's dementia by CSF? ß42,? ß42 /? ß40 ratio and total tau. Neurobiology of Aging (2004), 25 (3), p. 273-281; Olsson, A .; Hoglund, K .; Sjogren, M .; Andreasen, N .; Minthon, L .; Lannfelt, L .; Buerger, K .; Moller, H.-J .; Hampel, H .; Davidsson, P .; Blennow, K. (Sahlgrenska University Hospital, Experimental Neuroscience Section, Institute of Clinical Neuroscience, Goteborg University, Moelndal, Sweden), Measurement of a- and β-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients, Experimental Neurology (2003), 183 (1), p. 74-80; Wahlund, L.-O .; Blennow, K. (Karolinska Institute, Section of Geriatric Medicine, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, Stockholm, Sweden), Cerebrospinal fluid biomarkers for disease stage and intensity in coqnitively impaired patients, Neuroscience Letters (2003), 339 (2), pgs. 99-102; El Mouedden, M., Vandermeeren, M., Meert, T., Mercken, M. (Johnson &Johnson Pharmaceutical Research and Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, Belgium), Development of a specific ELISA for the quantitative study of amino-terminal truncated beta-amyloid peptides, Journal of Neuroscience Methods (2005), 145 (1-2), p. 97-105; Vanderstichele, H., Van Kerschaver, E., Hesse, C, Davidsson, P., Buyse, M.-A., Andreasen, N., Minthon, L., Wallin, A., Blennow, K., Vanmechelen, E., (Innogenetics NV, Ghent, Belg.), Standardization of measurement of B-amyloid (1-42) in cerebrospinal fluid and plasma, Amyloid (2000), 7 (4), p. 245-258; and / or Schoonenboom, NS, Mulder, C, Van Kamp, GJ, Mehta, SP, Scheltens, P., Blankenstein, MA, Mehta, PD, Amyloid 3 38, 40, and 42 species in cerebrospinal fluid: More of the same ?, Annals of Neurology (2005), 58 (1), p. 139-142.

Example 9. Predictive Example As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 2 or 3 were formulated with enough finely divided lactose to provide a total amount of 580 to 590 mg to complete the size of a capsule O-size hard gel. Although the above specification teaches the principles of the present invention with examples provided for purposes of illustration, it will be understood that the practice of the invention encompasses all customary variations, adaptations or modifications that fall within the scope of the invention. following claims and their equivalents.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. A compound of Formula (I) where a is an integer from 0 to 4; R1 is selected from the group consisting of halogen, C-u alkyl, C-M alkoxy, halogenated C-M alkyl and halogenated C-i-4 alkoxy; is selected from the group consisting of aryl and heteroaryl; R2 is selected from the group consisting of hydrogen and C-M alkoxy; R3 is selected from the group consisting of hydrogen, C-i-s alkyl, C2-alkyl substituted with hydroxy, substituted C2-8 alkyl in NRARB, -alkyl of Ci-4, cycloalkyl, - (alkyl of heterocycloalkyl and - (4,4-alkyl) -heterocycloalkyl; wherein RA and RB are independently selected from the group consisting of hydrogen and C1-4alkyl; A1 is selected from group consisting of - (CH2) b-; where b is an integer from 2 to 4; L1 is selected from the group consisting of -NRC- and -C (0) -NRC-; wherein RC is selected from the group consisting of hydrogen, C-ue alkyl, Ci ^-alkyl substituted with hydroxy, -alkyl of C-M-O-C1-4alkyl and C5-7 cycloalkyl; R 4 is selected from the group consisting of Ci-e alkyl, alkenyl of Ci-4-O-alkyl of alkyl of 1-4, -alkyl of Ci-4-NRDRE, -alkyl of C -OH, cycloalkyl, - alkyl of partially unsaturated carbocyclyl, -alkyl partially unsaturated), aryl, aralkyl, heteroaryl, -alkyl of C -heteroaryl, heterocycloalkyl and -C1-4alkyl-heterocycloalkyl; wherein RD and RE are independently selected from the group consisting of hydrogen and C1-4 alkyl; and wherein the cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, C1-4alkyl, -alkyl of Ci-4-O-alkyl of CM, carboxy, -C (0) 0-alkyl and aralkyl of alternatively, L is -NRC- and RC and R4 combine with the nitrogen atom to which they are attached to form an annular structure selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and 1- (1, 2,3- triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or 1- (1, 2,3-triazolyl) is optionally substituted with a substituent selected from the group consisting of Ci.6 alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, further characterized in that a is an integer from 0 to 3; R1 is selected from the group consisting of halogen, Ci-4 alkoxy, alkyl and halogenated alkoxy of C-M; is selected from the group consisting of aryl and heteroaryl; R2 is selected from the group consisting of hydrogen and Ci-4i alkoxy. R3 is selected from the group consisting of Cie alkyl, C2-8 alkyl substituted with hydroxy, substituted C2.8 alkyl in NRARB, cycloalkyl, - (alkyl) of Ci ^) - cycloalkyl, heterocycloalkyl and - (Ci-4 alkyl) -heterocycloalkyl; wherein RA and RB are independently selected from the group consisting of hydrogen and O- alkyl; A1 is selected from the group consisting of - (CH2) b-; where b is an integer from 2 to 4; L1 is selected from the group consisting of -NRC- and -C (0) -NRc-en wherein Rc is selected from the group consisting of hydrogen, C 1-8 alkyl, C 1 alkyl substituted with hydroxy and C 5 cycloalkyl .7; R 4 is selected from the group consisting of Cie alkyl, C 1-4 alkyl-C 1-4 alkyl, C 1-4 alkyl-NRDRE, C 1-4 alkyl-OH, cycloalkyl, alkyl of d. 4-cycloalkyl, aryl, aralkyl, heteroaryl, -C1-4alkyl-heteroaryl, heterocycloalkyl and -alkyl-heterocycloalkyl wherein RD and RE are independently selected from the group consisting of hydrogen and C- alkyl; and wherein the cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, C 1-4 alkyl, carboxy, -C (0) 0-alkyl and C1-4 aralkyl; alternatively, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form an annular structure selected from the group consisting of 1-pyrazolyl, 1-imidazolyl and 1- (1, 2,3- triazolyl); wherein the 1-pyrazolyl, 1-imidazolyl or 1- (1, 2,3-triazolyl) is optionally substituted with a substituent selected from the group consisting of Ci.6 alkyl; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, further characterized in that a is an integer from 0 to 2; R1 is selected from the group consisting of halogen, C1.2 alkoxy, alkyl and Ci.fluorinated alkoxy; is selected from the group consisting of aryl and heteroaryl; R2 is selected from the group consisting of hydrogen and C2-alkoxy; R3 is selected from the group consisting of cycloalkyl and heterocycloalkyl; A1 is selected from the group consisting of - (CH2) t >; further characterized in that b is an integer from 2 to 3; L1 is selected from the group consisting of -NRC- and -C (0) -NRc-; wherein R c is selected from the group consisting of hydrogen, C 1 e alkyl and cycloalkyl; R 4 is selected from the group consisting of Cie alkyl, C 1-6 alkyl substituted with hydroxy, Ci-4-O-alkyl of CM-, cycloalkyl, -Ci-2-cycloalkyl, aralkyl, heteroaryl, -Ci-2-heteroaryl and -alkyl heterocycloalkyl Ci-2 alkyl; wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, alone or as part of a substituent group, is optionally substituted with C- alkyl; alternatively, L1 is -NRC- and RC and R4 combine with the nitrogen atom to which they are attached to form 1- (1, 2,3-triazolyl); wherein 1,2,3-triazolyl is optionally substituted with a C 1-4 alkyl; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 3, further characterized in that a is an integer from 0 to 2; R1 is selected from the group consisting of fluorine, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy; is selected from the group consisting of phenyl, 2-thienyl, 2-pyrrolyl, 2-pyridyl and 7-indolyl; R2 is selected from the group consisting of hydrogen, methoxy and ethoxy; R3 is selected from the group consisting of (S) -cyclohexyl and 4-tetrahydropyranyl; A1 is selected from the group consisting of -CH2CH2- and -CH2CH2CH2-; L1 is selected from the group consisting of -NRC- and -C (0) -NRc-; wherein R c is selected from the group consisting of hydrogen, methyl, 3,3-dimethyl-n-butyl and cyclohexyl; R4 is selected from the group consisting of 1- (3,3, -dimethyl-n-butyl), 1-hydroxyethyl-, 1- (2,2-dimethyl-3-hydroxy-n-propyl), t-butoxyethyl, cyclohexyl, 1-adamantyl, cyclopropylmethyl-, cyclohexylmethyl -, benzyl, 2- (1-methylimidazolyl), 2-pyridylmethyl-, 1-pyrrolidinylethyl-, 5-thiazolyl-methyl- and 4-morpholinylethyl-; alternatively, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form 1- (4-t-butyl-1,2,3-triazolyl); or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, further characterized in that a is an integer from 1 to 2; R1 is selected from the group consisting of fluorine, methoxy and ethoxy; is selected from the group consisting of phenyl and 2-thienyl; R2 is selected from the group consisting of hydrogen, methoxy and ethoxy; R3 is 4-tetrahydropyranyl; A1 is selected from the group consisting of -CH2CH2- and -CH2CH2CH2-; L is selected from the group consisting of -NRC- and -C (0) -NRc-; wherein R c is selected from the group consisting of hydrogen, 3,3-dimethyl-n-butyl and cyclohexyl; R 4 is selected from the group consisting of 1- (3,3-dimethyl-n-butyl), t-butoxyethyl, 1-adamantyl, cyclohexylmethyl-, benzyl, 2- (1-methylimidazolyl), 2-pyridylmethyl-, 1- pyrrolidinylethyl-, 5-thiazolylmethyl- and 4-morpholinylethyl-; alternatively, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form 1- (4-t-butyl-1,2,3-triazolyl); or a pharmaceutically acceptable salt thereof. The compound according to claim further characterized in that a is an integer from 1 to 2; R1 is selected from the group consisting of fluorine and ethoxy; is selected from the group consisting of phenyl and 2-thienyl; R2 is hydrogen; R3 is 4-tetrahydropyranyl; A1 is -CH2CH2-; L is -C (0) -NRc-; wherein R c is selected from the group consisting of hydrogen, 3,3-dimethyl-n-butyl and cyclohexyl; R 4 is selected from the group consisting of 1- (3,3-dimethyl-n-butyl), cyclohexylmethyl-, benzyl, 2- (1-methylimidazolyl), 2-pyridylmethyl-, 1-pyrrolidinylethyl-, 5-thiazolylmethyl- and 4-morpholinylethyl-; or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 4, further characterized in that a is 1; R1 is selected from the group consisting of fluorine, methoxy and trifluoromethoxy is selected from the group consisting of phenyl, 2-thienyl and 7-indolyl; R2 is selected from the group consisting of hydrogen and ethoxy; R3 is 4-tetrahydropyranyl; A1 is selected from the group consisting of -CH2CH2- and -CH2CH2CH2-; L1 is selected from the group consisting of -NRC- and -C (0) -NRc- ; wherein R c is selected from the group consisting of hydrogen, methyl and 3,3-dimethyl-n-butyl; R 4 is selected from the group consisting of 1- (3,3, -dimethyl-n-butyl), 1-adamantyl, cyclohexylmethyl-, 2- (1-methylimidazolyl), 5-thiazolylmethyl- and 4-morpholinylethyl-; alternatively, L1 is -NRC- and Rc and R4 combine with the nitrogen atom to which they are attached to form 1- (4-t-butyl-1,2,3-triazolyl); or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 4, further characterized in that a is 1; R1 is selected from the group consisting of fluorine, methoxy and trifluoromethoxy is selected from the group consisting of phenyl and 7-indolyl; R2 is hydrogen; R3 is 4-tetrahydropyranyl; A1 is selected from the group consisting of -CH2CH2- and -CH2CH2CH2-; L1 is selected from the group consisting of -NRC- and -C (O) -NRC-; further characterized in that Rc is selected from the group consisting of hydrogen, methyl and 3,3-dimethyl-n-butyl; R 4 is selected from the group consisting of 1- (3,3, -dimethyl-n-butyl), 1-adamantyl, cyclohexylmethyl-, 2- (1-methylimidazolyl), 5-thiazolylmethyl- and 4-morpholinylethyl-; or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. 10. A pharmaceutical composition that is made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier. 11. A process for making a pharmaceutical composition; the process comprises mixing a compound of claim 1 and a pharmaceutically acceptable carrier. 12. The use of the compound of claim 1, for preparing a medicament for treating a disorder mediated by β-secretase in a subject. 13. The use as claimed in claim 12, wherein the disorder mediated by β-secretase is selected from the group consisting of Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies. , Down syndrome, dementia associated with CVA, dementia associated with Parkinson's disease and dementia associated with beta-amyloid. The use of the composition of claim 9, for preparing a medicament for treating a disorder mediated by β-secretase in a subject. 15. The use of any of the compounds of claim 1, for preparing a medicament for inhibiting the β-secretase enzyme in a subject. 16. The use of a compound of claim 1 for preparing a medicament for treating: (a) Alzheimer's disease (AD), (b) mild cognitive impairment, (c) senility, (d) dementia, (e) dementia with Lewy bodies, (f) Down syndrome, (g) dementia associated with CVA, (h) associated dementia to Parkinson's disease and (i) dementia associated with beta-amyloid, subject who needs the medication.